Association Between Hormone Therapy and Muscle Mass in Postmenopausal Women: A Systematic Review and Meta-analysis | Clinical Pharmacy and Pharmacology | JAMA Network Open | JAMA Network
[Skip to Navigation]
[Skip to Navigation Landing]
Figure 1.  Flow Diagram of the Literature Screening Process
Flow Diagram of the Literature Screening Process

HT indicates hormone therapy; RCTs, randomized clinical trials; and SDs, standard deviations.

Figure 2.  Summary Meta-analysis of the Association Between Hormone Therapy (HT) Intervention and Muscle Mass Outcomes
Summary Meta-analysis of the Association Between Hormone Therapy (HT) Intervention and Muscle Mass Outcomes

The forest plot of the overall meta-analyses of all included studies presents the mean (95% CI) differences for lean body mass between women receiving HT and women not receiving HT. Size of data marker indicates relative weighting of study.

Table 1.  Study Characteristicsa
Study Characteristicsa
Table 2.  Muscle Mass Outcome Measures
Muscle Mass Outcome Measures
Supplement.

eTable 1. Electronic Search Strategies for Databases MEDLINE, Embase, AgeLine, CINAHL, and SportDiscus

eTable 2. Estrogen Dose Equivalence Calculations

eTable 3. Study Characteristics (Part 1)

eTable 4. Study Characteristics (Part 2)

eTable 5. Study Characteristics (Part 3)

eTable 6. Risk of Bias Assessment

eTable 7. Summary Meta-analysis of the Association Between Less Than 0.625 mg Estrogen-Only Treatment and Muscle Mass Outcomes

eTable 8. Summary Meta-analysis of the Association Between 0.625 mg or More Estrogen-Only Treatment and Muscle Mass Outcomes

eTable 9. Summary Meta-analysis of the Association Between Less than 0.625 mg Estrogen + Any Dose Progesterone Treatment and Muscle Mass Outcomes

eTable 10. Summary Meta-analysis of the Association Between 0.625 mg or More Estrogen + Any Dose Progesterone Treatment and Muscle Mass Outcomes

eTable 11. Summary Meta-analysis of the Association Between Shorter Follow-up Lengths and Muscle Mass Outcomes

eTable 12. Summary Meta-analysis of the Association Between Longer Follow-up Lengths and Muscle Mass Outcomes

eTable 13. Summary Meta-analysis of Studies With <10 Years of Time Since Menopause

eTable 14. Summary Meta-analysis of the Association Between Shorter Times Since Menopause and Muscle Mass Outcomes

eTable 15. Summary Meta-analysis of the Association Between Longer Times Since Menopause and Muscle Mass Outcomes

eTable 16. Summary Meta-analysis of the Association Between Fair/Good Study Quality and Muscle Mass Outcomes

eTable 17. Summary Meta-analysis of the Association Between Poor Study Quality and Muscle Mass Outcomes

eTable 18. Summary Meta-analysis of the Association Between DEXA Measurement and Muscle Mass Outcomes

eTable 19. Summary Meta-analysis of the Association Between Other Measurement and Muscle Mass Outcomes

eTable 20. GRADE Assessment

eFigure. Funnel Plot for Assessment of Publication Bias

1.
World Health Organization. Ageing and health. https://www.who.int/ageing/publications/global_health.pdf?ua. Published 2018. Acccessed May 25, 2018.
2.
Austad  SN.  Why women live longer than men: sex differences in longevity.  Gend Med. 2006;3(2):79-92. doi:10.1016/S1550-8579(06)80198-1PubMedGoogle Scholar
3.
Kirchengast  S, Huber  J.  Gender and age differences in lean soft tissue mass and sarcopenia among healthy elderly.  Anthropol Anz. 2009;67(2):139-151. doi:10.1127/0003-5548/2009/0018PubMedGoogle Scholar
4.
Shafiee  G, Keshtkar  A, Soltani  A, Ahadi  Z, Larijani  B, Heshmat  R.  Prevalence of sarcopenia in the world: a systematic review and meta-analysis of general population studies.  J Diabetes Metab Disord. 2017;16(1):21. doi:10.1186/s40200-017-0302-xPubMedGoogle Scholar
5.
Takahashi  TA, Johnson  KM.  Menopause.  Med Clin North Am. 2015;99(3):521-534. doi:10.1016/j.mcna.2015.01.006PubMedGoogle Scholar
6.
Janssen  I, Heymsfield  SB, Ross  R.  Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability.  J Am Geriatr Soc. 2002;50(5):889-896. doi:10.1046/j.1532-5415.2002.50216.xPubMedGoogle Scholar
7.
Scott  D, Hayes  A, Sanders  KM, Aitken  D, Ebeling  PR, Jones  G.  Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults.  Osteoporos Int. 2014;25(1):187-193. doi:10.1007/s00198-013-2431-5PubMedGoogle Scholar
8.
Landi  F, Liperoti  R, Russo  A,  et al.  Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study.  Clin Nutr. 2012;31(5):652-658. doi:10.1016/j.clnu.2012.02.007PubMedGoogle Scholar
9.
Tanimoto  Y, Watanabe  M, Sun  W,  et al.  Sarcopenia and falls in community-dwelling elderly subjects in Japan: defining sarcopenia according to criteria of the European Working Group on Sarcopenia in Older People.  Arch Gerontol Geriatr. 2014;59(2):295-299. doi:10.1016/j.archger.2014.04.016PubMedGoogle Scholar
10.
Gariballa  S, Alessa  A.  Sarcopenia: prevalence and prognostic significance in hospitalized patients.  Clin Nutr. 2013;32(5):772-776. doi:10.1016/j.clnu.2013.01.010PubMedGoogle Scholar
11.
Kim  JH, Lim  S, Choi  SH,  et al.  Sarcopenia: an independent predictor of mortality in community-dwelling older Korean men.  J Gerontol A Biol Sci Med Sci. 2014;69(10):1244-1252. doi:10.1093/gerona/glu050PubMedGoogle Scholar
12.
Landi  F, Cruz-Jentoft  AJ, Liperoti  R,  et al.  Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study.  Age Ageing. 2013;42(2):203-209. doi:10.1093/ageing/afs194PubMedGoogle Scholar
13.
Tankó  LB, Movsesyan  L, Svendsen  OL, Christiansen  C.  The effect of hormone replacement therapy on appendicular lean tissue mass in early postmenopausal women.  Menopause. 2002;9(2):117-121. doi:10.1097/00042192-200203000-00006PubMedGoogle Scholar
14.
Brown  M, Birge  SJ, Kohrt  WM.  Hormone replacement therapy does not augment gains in muscle strength or fat-free mass in response to weight-bearing exercise.  J Gerontol A Biol Sci Med Sci. 1997;52(3):B166-B170. doi:10.1093/gerona/52A.3.B166PubMedGoogle Scholar
15.
Dayal  M, Sammel  MD, Zhao  J, Hummel  AC, Vandenbourne  K, Barnhart  KT.  Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids.  J Womens Health (Larchmt). 2005;14(5):391-400. doi:10.1089/jwh.2005.14.391PubMedGoogle Scholar
16.
Dobs  AS, Nguyen  T, Pace  C, Roberts  CP; AS D.  Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women.  J Clin Endocrinol Metab. 2002;87(4):1509-1516. doi:10.1210/jcem.87.4.8362PubMedGoogle Scholar
17.
Greeves  JP, Cable  NT, Reilly  T, Kingsland  C.  Changes in muscle strength in women following the menopause: a longitudinal assessment of the efficacy of hormone replacement therapy.  Clin Sci (Lond). 1999;97(1):79-84. doi:10.1042/cs0970079PubMedGoogle Scholar
18.
North American Menopause Society. The experts do agree about hormone therapy. http://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/the-experts-do-agree-about-hormone-therapy. Published 2019. Accessed July 23, 2019.
19.
Bemben  DA, Langdon  DB.  Relationship between estrogen use and musculoskeletal function in postmenopausal women.  Maturitas. 2002;42(2):119-127. doi:10.1016/S0378-5122(02)00033-6PubMedGoogle Scholar
20.
Taaffe  DR, Newman  AB, Haggerty  CL,  et al.  Estrogen replacement, muscle composition, and physical function: The Health ABC Study.  Med Sci Sports Exerc. 2005;37(10):1741-1747. doi:10.1249/01.mss.0000181678.28092.31PubMedGoogle Scholar
21.
Lemoine  S, Granier  P, Tiffoche  C, Rannou-Bekono  F, Thieulant  ML, Delamarche  P.  Estrogen receptor alpha mRNA in human skeletal muscles.  Med Sci Sports Exerc. 2003;35(3):439-443. doi:10.1249/01.MSS.0000053654.14410.78PubMedGoogle Scholar
22.
Dubé  JY, Lesage  R, Tremblay  RR.  Androgen and estrogen binding in rat skeletal and perineal muscles.  Can J Biochem. 1976;54(1):50-55. doi:10.1139/o76-008PubMedGoogle Scholar
23.
VanBrocklin  HF, Pomper  MG, Carlson  KE, Welch  MJ, Katzenellenbogen  JA.  Preparation and evaluation of 17-ethynyl-substituted 16 α-[18F]fluoroestradiols: selective receptor-based PET imaging agents.  Int J Rad Appl Instrum B. 1992;19(3):363-374. doi:10.1016/0883-2897(92)90122-FPubMedGoogle Scholar
24.
Friend  KE, Hartman  ML, Pezzoli  SS, Clasey  JL, Thorner  MO.  Both oral and transdermal estrogen increase growth hormone release in postmenopausal women—a clinical research center study.  J Clin Endocrinol Metab. 1996;81(6):2250-2256.PubMedGoogle Scholar
25.
Dionne  IJ, Kinaman  KA, Poehlman  ET.  Sarcopenia and muscle function during menopause and hormone-replacement therapy.  J Nutr Health Aging. 2000;4(3):156-161.PubMedGoogle Scholar
26.
D’Eon  T, Braun  B.  The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise.  J Womens Health Gend Based Med. 2002;11(3):225-237. doi:10.1089/152460902753668439PubMedGoogle Scholar
27.
Rossouw  JE, Anderson  GL, Prentice  RL,  et al; Writing Group for the Women’s Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.  JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321PubMedGoogle Scholar
28.
Hodis  HN, Mack  WJA.  A “window of opportunity”: the reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent.  Brain Res. 2011;1379:244-252. doi:10.1016/j.brainres.2010.10.076PubMedGoogle Scholar
29.
Hodis  HN, Collins  P, Mack  WJ, Schierbeck  LL.  The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective.  Climacteric. 2012;15(3):217-228. doi:10.3109/13697137.2012.656401PubMedGoogle Scholar
30.
Sipilä  S, Poutamo  J.  Muscle performance, sex hormones and training in peri-menopausal and post-menopausal women.  Scand J Med Sci Sports. 2003;13(1):19-25. doi:10.1034/j.1600-0838.2003.20210.xPubMedGoogle Scholar
31.
Greising  SM, Baltgalvis  KA, Lowe  DA, Warren  GL.  Hormone therapy and skeletal muscle strength: a meta-analysis.  J Gerontol A Biol Sci Med Sci. 2009;64(10):1071-1081. doi:10.1093/gerona/glp082PubMedGoogle Scholar
32.
Tiidus  PM.  Benefits of estrogen replacement for skeletal muscle mass and function in post-menopausal females: evidence from human and animal studies.  Eurasian J Med. 2011;43(2):109-114. doi:10.5152/eajm.2011.24PubMedGoogle Scholar
33.
Gambacciani  M, Ciaponi  M, Cappagli  B, De Simone  L, Orlandi  R, Genazzani  AR.  Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.  Maturitas. 2001;39(2):125-132. doi:10.1016/S0378-5122(01)00194-3PubMedGoogle Scholar
34.
Baumgartner  RN, Waters  DL, Gallagher  D, Morley  JE, Garry  PJ.  Predictors of skeletal muscle mass in elderly men and women.  Mech Ageing Dev. 1999;107(2):123-136. doi:10.1016/S0047-6374(98)00130-4PubMedGoogle Scholar
35.
Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100PubMedGoogle Scholar
36.
Evidence Partners. DistillerSR: better, faster systematic reviews used systematic review software. https://www.evidencepartners.com/products/distillersr-systematic-review-software/. Published 2011. Accessed April 25, 2018.
37.
Higgins  JPT, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343(7829):d5928. doi:10.1136/bmj.d5928PubMedGoogle Scholar
38.
Guyatt  G, Oxman  AD, Akl  EA,  et al.  GRADE guidelines: 1, introduction-GRADE evidence profiles and summary of findings tables.  J Clin Epidemiol. 2011;64(4):383-394. doi:10.1016/j.jclinepi.2010.04.026PubMedGoogle Scholar
39.
Guyatt  GH, Oxman  AD, Vist  GE,  et al; GRADE Working Group.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.  BMJ. 2008;336(7650):924-926. doi:10.1136/bmj.39489.470347.ADPubMedGoogle Scholar
40.
Stuck  AE, Rubenstein  LZ, Wieland  D.  Bias in meta-analysis detected by a simple, graphical test: asymmetry detected in funnel plot was probably due to true heterogeneity.  BMJ. 1998;316(7129):469-471. doi:10.1136/bmj.316.7129.469PubMedGoogle Scholar
41.
Begg  CB, Mazumdar  M.  Operating characteristics of a rank correlation test for publication bias.  Biometrics. 1994;50(4):1088-1101. doi:10.2307/2533446PubMedGoogle Scholar
42.
Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen, Denmark: Nordic Cochrane Centre, Cochrane Collaboration; 2014.
43.
Gambacciani  M, Genazzani  AR.  Hormone replacement therapy: the benefits in tailoring the regimen and dose.  Maturitas. 2001;40(3):195-201. doi:10.1016/S0378-5122(01)00281-XPubMedGoogle Scholar
44.
Lindsay  R, Hart  DM, Clark  DM.  The minimum effective dose of estrogen for prevention of postmenopausal bone loss.  Obstet Gynecol. 1984;63(6):759-763.PubMedGoogle Scholar
45.
Panay  N, Ylikorkala  O, Archer  DF, Gut  R, Lang  E.  Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief.  Climacteric. 2007;10(2):120-131. doi:10.1080/13697130701298107PubMedGoogle Scholar
46.
Bea  JW, Zhao  Q, Cauley  JA,  et al.  Effect of hormone therapy on lean body mass, falls, and fractures: 6-year results from the Women’s Health Initiative hormone trials.  Menopause. 2011;18(1):44-52. doi:10.1097/gme.0b013e3181e3aab1PubMedGoogle Scholar
47.
Blackman  MR, Sorkin  JD, Münzer  T,  et al.  Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial.  JAMA. 2002;288(18):2282-2292. doi:10.1001/jama.288.18.2282PubMedGoogle Scholar
48.
Haarbo  J, Marslew  U, Gotfredsen  A, Christiansen  C.  Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause.  Metabolism. 1991;40(12):1323-1326. doi:10.1016/0026-0495(91)90037-WPubMedGoogle Scholar
49.
Jensen  LB, Vestergaard  P, Hermann  AP,  et al.  Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study.  J Bone Miner Res. 2003;18(2):333-342. doi:10.1359/jbmr.2003.18.2.333PubMedGoogle Scholar
50.
Kenny  AM, Kleppinger  A, Wang  Y, Prestwood  KM.  Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women.  J Am Geriatr Soc. 2005;53(11):1973-1977. doi:10.1111/j.1532-5415.2005.53567.xPubMedGoogle Scholar
51.
Pöllänen  E, Ronkainen  PH, Suominen  H,  et al.  Muscular transcriptome in postmenopausal women with or without hormone replacement.  Rejuvenation Res. 2007;10(4):485-500. doi:10.1089/rej.2007.0536PubMedGoogle Scholar
52.
Sipilä  S, Taaffe  DR, Cheng  S, Puolakka  J, Toivanen  J, Suominen  H.  Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study.  Clin Sci (Lond). 2001;101(2):147-157. doi:10.1042/cs1010147PubMedGoogle Scholar
53.
Thorneycroft  IH, Lindsay  R, Pickar  JH.  Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial.  Am J Obstet Gynecol. 2007;197(2):137.e1-137.e7. doi:10.1016/j.ajog.2007.05.042PubMedGoogle Scholar
54.
de Villiers  TJ, Pines  A, Panay  N,  et al; International Menopause Society.  Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health.  Climacteric. 2013;16(3):316-337. doi:10.3109/13697137.2013.795683PubMedGoogle Scholar
55.
Santen  RJ, Allred  DC, Ardoin  SP,  et al; Endocrine Society.  Postmenopausal hormone therapy: an Endocrine Society scientific statement.  J Clin Endocrinol Metab. 2010;95(7)(suppl 1):s1-s66. doi:10.1210/jc.2009-2509PubMedGoogle Scholar
56.
Branski  LK, Norbury  WB, Herndon  DN,  et al.  Measurement of body composition in burned children: is there a gold standard?  JPEN J Parenter Enteral Nutr. 2010;34(1):55-63. doi:10.1177/0148607109336601PubMedGoogle Scholar
57.
Chen  Z, Bassford  T, Green  SB,  et al.  Postmenopausal hormone therapy and body composition—a substudy of the estrogen plus progestin trial of the Women’s Health Initiative.  Am J Clin Nutr. 2005;82(3):651-656. doi:10.1093/ajcn/82.3.651PubMedGoogle Scholar
58.
Hassager  C, Christiansen  C.  Estrogen/gestagen therapy changes soft tissue body composition in postmenopausal women.  Metabolism. 1989;38(7):662-665. doi:10.1016/0026-0495(89)90104-2PubMedGoogle Scholar
59.
Sørensen  MB, Rosenfalck  AM, Højgaard  L, Ottesen  B.  Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy.  Obes Res. 2001;9(10):622-626. doi:10.1038/oby.2001.81PubMedGoogle Scholar
60.
Aloia  JF, Vaswani  A, Russo  L, Sheehan  M, Flaster  E.  The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass.  Am J Obstet Gynecol. 1995;172(3):896-900. doi:10.1016/0002-9378(95)90018-7PubMedGoogle Scholar
61.
Evans  EM, Van Pelt  RE, Binder  EF, Williams  DB, Ehsani  AA, Kohrt  WM.  Effects of HRT and exercise training on insulin action, glucose tolerance, and body composition in older women.  J Appl Physiol (1985). 2001;90(6):2033-2040. doi:10.1152/jappl.2001.90.6.2033PubMedGoogle Scholar
62.
Washburn  RA, Smith  KW, Jette  AM, Janney  CA.  The Physical Activity Scale for the Elderly (PASE): development and evaluation.  J Clin Epidemiol. 1993;46(2):153-162. doi:10.1016/0895-4356(93)90053-4PubMedGoogle Scholar
63.
Goodpaster  BH, Park  SW, Harris  TB,  et al.  The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.  J Gerontol A Biol Sci Med Sci. 2006;61(10):1059-1064. doi:10.1093/gerona/61.10.1059PubMedGoogle Scholar
64.
von Haehling  S, Morley  JE, Anker  SD.  An overview of sarcopenia: facts and numbers on prevalence and clinical impact.  J Cachexia Sarcopenia Muscle. 2010;1(2):129-133. doi:10.1007/s13539-010-0014-2PubMedGoogle Scholar
65.
Bea  JW, Thomson  CA, Wertheim  BC,  et al.  Risk of mortality according to body mass index and body composition among postmenopausal women.  Am J Epidemiol. 2015;182(7):585-596. doi:10.1093/aje/kwv103PubMedGoogle Scholar
66.
Barhum  BL, Marcin  J. What is the average height for women? https://www.medicalnewstoday.com/articles/321132.php. Accessed April 25, 2018.
67.
Coraci  D, Santilli  V, Padua  L.  Comment on “Cut-off points to identify sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP) definition.”  Clin Nutr. 2016;35(6):1568-1569. doi:10.1016/j.clnu.2016.06.026PubMedGoogle Scholar
68.
Maltais  ML, Desroches  J, Dionne  IJ.  Changes in muscle mass and strength after menopause.  J Musculoskelet Neuronal Interact. 2009;9(4):186-197.PubMedGoogle Scholar
69.
Ryan  AS, Pratley  RE, Elahi  D, Goldberg  AP.  Resistive training increases fat-free mass and maintains RMR despite weight loss in postmenopausal women.  J Appl Physiol (1985). 1995;79(3):818-823. doi:10.1152/jappl.1995.79.3.818PubMedGoogle Scholar
70.
Goulet  ED, Mélançon  MO, Dionne  IJ, Aubertin-Leheudre  M.  No sustained effect of aerobic or resistance training on insulin sensitivity in nonobese, healthy older women.  J Aging Phys Act. 2005;13(3):314-326. doi:10.1123/japa.13.3.314PubMedGoogle Scholar
71.
Figueroa  A, Going  SB, Milliken  LA,  et al.  Effects of exercise training and hormone replacement therapy on lean and fat mass in postmenopausal women.  J Gerontol A Biol Sci Med Sci. 2003;58(3):266-270. doi:10.1093/gerona/58.3.M266PubMedGoogle Scholar
72.
Newman  AB, Kupelian  V, Visser  M,  et al.  Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort.  J Gerontol A Biol Sci Med Sci. 2006;61(1):72-77. doi:10.1093/gerona/61.1.72PubMedGoogle Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    Hormones and muscle mass postmenopause
    Dr Hana Fayyad, M.D. | Hammoud Hospital-Lebanon
    Physical activity and healthy food remains the best means to ameliorate muscle loss. Interestingly, a study comparing adult diets which included 10 olives daily, with no-olives diet, revealed significantly more muscle -mass gain in the olive-intake group; it seems though olives are not protein-rich, perhaps the monounsaturated fat therein plays a role in improved incorporation of muscle.
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    Geriatrics
    August 28, 2019

    Association Between Hormone Therapy and Muscle Mass in Postmenopausal Women: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1McMaster Institute for Research on Aging, McMaster University, Hamilton, Ontario, Canada
    • 2Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
    • 3Labarge Centre for Mobility in Aging, McMaster University, Hamilton, Ontario, Canada
    • 4Department of Obstetrics and Gynecology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
    JAMA Netw Open. 2019;2(8):e1910154. doi:10.1001/jamanetworkopen.2019.10154
    Key Points español 中文 (chinese)

    Question  In postmenopausal women 50 years or older, is estrogen-based hormone therapy associated with reduced loss of lean body mass compared with no hormone therapy?

    Findings  In this systematic review and meta-analysis of 12 studies comprising 4474 postmenopausal women, those who received estrogen-based hormone therapy lost less lean body mass compared with women who received no hormone therapy and women who received placebo, but this finding was not statistically significant.

    Meaning  The importance of muscle retention in aging women is crucial, but these findings suggest that interventions other than hormone therapy should be explored.

    Abstract

    Importance  Hormone therapy (HT) has been suggested for protection against age-related muscle weakness in women. However, the potential for HT-associated health risks necessitates a better understanding of the direction and magnitude of the association between HT and health outcomes, such as lean body mass (LBM).

    Objective  To determine whether HT was associated with reduced LBM loss compared with not receiving HT among postmenopausal women aged 50 years and older.

    Data Sources  MEDLINE, Embase, AgeLine, CINAHL, and SportDiscus (searched from inception until April 25, 2018).

    Study Selection  For this systematic review and meta-analysis, randomized clinical trials including postmenopausal women undergoing HT and control groups of women not receiving HT were selected by 2 reviewers. Studies were included if LBM or fat-free mass were measured as an outcome. Studies with participants from hospitals, long-term care facilities, or with specific diseases were excluded.

    Data Extraction and Synthesis  Information regarding study characteristics and outcome measures were extracted by 1 reviewer and verified by another. Risk of bias was evaluated. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used to abstract data and assess data quality/validity. Data were pooled using a fixed-effects model.

    Main Outcomes and Measures  The primary study outcome was the overall absolute change in LBM (measured in kilograms), captured by dual-energy x-ray absorptiometry, dual-photon absorptiometry, or bioelectrical impedance analysis imaging.

    Results  Of 8961 studies that met selection criteria, 12 were included, with a total of 4474 recruited participants. Of the participants, mean (SD) age was 59.0 (6.1) years. Data on ethnicity were collected by 2 of the studies. Of the 22 HT intervention arms, 15 used estrogen-progesterone combination HT and 7 used estrogen-only HT. Control participants were women who received no HT at all or who received placebo. The median follow-up duration was 2 years (range, 6 months to 6 years). Seven treatment arms showed a loss of LBM, and 14 were protective. Overall, HT users lost 0.06 kg (95% CI, –0.05 to 0.18) less LBM compared with control participants, but the difference was not statistically significant (P = .26). The results were unchanged when stratified based on treatment type and dosage, duration of follow-up, time since menopause, study quality, and type of LBM measurement, with HT users losing between 0.06 kg more to 0.20 kg less LBM compared with control participants for all strata. The quality of evidence based on GRADE was low.

    Conclusions and Relevance  This systematic review and meta-analysis did not show a significant beneficial or detrimental association of HT with muscle mass. Although muscle retention in aging women is of crucial importance, these findings suggest that interventions other than HT should be explored.

    Introduction

    In 2015, adults 60 years and older composed 12% of the global population. By the year 2050, it is estimated that older adults will compose 22% of the world’s population, numbering approximately 2 billion people.1 Women have a longer life expectancy than men but experience more chronic, non–life-threatening illness after the age of 45 years.2 One such condition is the age-related decline in muscle mass and strength, called sarcopenia. High rates of sarcopenia have been observed in women 60 years and older, and it is hypothesized that the hormone changes occurring at menopause (between 49 and 52 years) may be responsible.3-5 Individuals with sarcopenia have a greater risk for poor health outcomes, including disability and functional impairments, increased risk of falls, longer hospital stays, and an increased risk of mortality.6-12 Because women live longer than men, women are more likely to experience the negative muscular changes that occur with aging that are strong predictors of mobility and functional impairment.

    Accelerated muscle loss, such as that of sarcopenia, has been associated with the menopausal transition and thus linked to declining estrogen levels.13-16 Therefore, hormone therapy (HT) has been suggested as a potential intervention.17 Hormone therapy is a method of estrogen supplementation, with or without progesterone, prescribed to manage and treat menopausal symptoms.18 However, the exact mechanism between estrogen and muscle mass maintenance has remained elusive.14,19,20 Estrogen may be directly involved in muscle metabolism through estrogen receptors found on skeletal muscle,14,20-23 as well as indirectly through the somatotropic axis by altering secretions of growth hormone and insulin growth factor 1.19,20,24,25 Also, estrogen plays a role in regulating carbohydrate and lipid metabolism by relieving muscle glycogen and prompting lipid oxidation,20,26 which could influence skeletal muscle composition in postmenopausal women.

    Despite the potential benefits of HT, data from the Women’s Health Initiative (WHI) study suggested that there may be increased risks associated with HT if started at a later age (ie, after 60 years), including a small increase in risk for stroke and venous thromboembolism.27 After the initial publication of the WHI results, a large proportion of women stopped their HT and many health care practitioners were anxious about prescribing HT, despite the relative safety for younger (early menopausal) women. During the window of opportunity in the first 10 years after menopause, HT has multiple health benefits, including relief from menopausal symptoms and reduced risks for coronary heart disease and all-cause mortality.18,28,29 However, to our knowledge, there is a lack of consensus among reviews regarding the role of HT in attenuating muscle mass loss. Several reviews have investigated the association between HT use and muscle mass and strength. Some of these reviews have included studies examining resistance training exercise interventions in addition to HT or evaluated muscle performance rather than muscle mass or strength, whereas others have included animal studies to supplement findings in human populations.30-32 Generally, these reviews have found that HT provides a small, significant benefit in preserving muscle strength (effect size: 0.23; P < .05),31 and that these benefits may be compounded when HT is used in conjunction with exercise training.30 There is also some evidence to suggest that HT may have beneficial effects on muscle mass.32 Some observational studies and randomized clinical trials have shown benefits of estrogen therapy on muscle mass in postmenopausal women,16,33 while others have not.13,14,20,34 However, to our knowledge, there is no systematic review published that has evaluated the independent association between HT use and muscle mass.

    The goal of this systematic review and meta-analyses was to determine whether, in postmenopausal women, HT (estrogen only or a combination of estrogen and progesterone) was associated with a reduced loss of muscle mass (measured by lean body mass [LBM] or fat-free mass), compared with not receiving HT, in relation to type and dose of HT, follow-up duration of study, menopausal age of participants, and type of LBM measurement.

    Methods

    This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.35 This review was registered in PROSPERO (CRD42016052047), the international prospective register of systematic reviews, on November 30, 2016. Ethics approval was not required for this research.

    Data Sources and Searches

    An electronic search strategy was developed to identify human studies investigating the association of HT use in postmenopausal women with LBM. On April 25, 2018, the following electronic databases were searched from inception to April 25, 2018: MEDLINE, Embase (Excerpta Medica Database), AgeLine, CINAHL (Cumulative Index to Nursing and Allied Health), and SportDiscus databases (eTable 1 in the Supplement). The reference lists of all the included studies were also reviewed.

    Inclusion and Exclusion Criteria

    Studies were included if participants were community-dwelling postmenopausal women aged 50 years or older who were receiving estrogen-based or estrogen-progesterone–based HT. Studies with participants from hospitals and long-term care facilities, or with specific conditions (breast or other cancer, Turner syndrome, or anorexia) were excluded. No restrictions were placed on the geographic, socioeconomic, or ethnic backgrounds of any of the participants.

    Eligible treatments included estrogen-based or estrogen-progesterone–based HT. No other restrictions were placed on HT administration.

    Only randomized clinical trials that were complete and published in full were eligible for inclusion in this review. The studies must have conducted primary research in human populations. Animal studies were excluded. We did not place any restrictions on the date of study or publication. Studies were limited to original English-language articles.

    Studies were included if LBM or fat-free mass was measured as an outcome. Lean body mass outcomes included measures from body scanning equipment including dual-energy x-ray absorptiometry (DEXA, or DXA), bioelectrical impedance analysis, magnetic resonance imaging, dual-photon absorptiometry, or computed tomography. Studies using muscle circumference or skin calipers for LBM measures were excluded.

    Study Selection

    Two independent reviewers (A.A.J. and A.J.M.) screened articles in duplicate at the title and abstract and full-text stages of the review. Screening of studies was conducted using the systematic review software DistillerSR version 2.0 (Evidence Partners).36

    Any potential conflicts between the reviewers were resolved through discussion. If discrepancies in judgment remain after discussion, a third-party reviewer (P.R.) was consulted to resolve the conflict and provide a final decision.

    Data Extraction

    One author (A.A.J.) independently extracted data from the included studies in DistillerSR, and the second author (A.M.) performed verification. Information about the study characteristics, including study date, country of conduct, sample size, age of participants, ethnicity, type of menopause (natural or induced), time since menopause, HT information (type, dose, and duration), type of comparison group, and duration of follow-up, was extracted.

    The type of scanning equipment (name, model, coefficient of variation of instrument, timing of measurement) was extracted, as well as LBM values at baseline, all available follow-up, and any data about the amount of change in LBM and P values for that change. Any conflicts were resolved through discussion. The third reviewer (P.R.) was consulted if a final decision was required in regard to said disagreements.

    Assessment of Risk of Bias

    The 2 independent reviewers (A.A.J. and A.J.M.) assessed the quality of the included studies in duplicate, using the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials.37 Any discrepancies between the independent reviewers were resolved by discussion. If conflicts were not adequately resolved through discussion, a third-party reviewer (P.R.) was consulted to resolve said disagreement. The assessment of risk of bias was completed at the study level.

    Grading of Recommendations Assessment, Development and Evaluation

    The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence by outcome.38,39 In GRADE, all randomized clinical trials begin with a grade of high and are downgraded based on the presence of risk of bias, inconsistency, indirectness, imprecision, or publication bias. Presence of each factor downgrades study quality by 1 level. The assessment was conducted across all studies, and then further stratified by subgroups. The quality-of-evidence decisions were reviewed and agreed on by both reviewers (A.A.J. and A.J.M.).

    The quality of evidence was categorized into 4 levels: very low, low, moderate, and high. Evidence was downgraded for risk of bias if there was evidence of selection, performance, attrition, reporting, or other bias. Evidence was downgraded for inconsistency if the I2 statistic for the mean difference estimate was greater than 50%, for indirectness if substantial differences existed between the population, intervention, or outcome or if indirect comparisons were used to make inferences about interventions of interest, and imprecision if the optimal information size (400 cases total, with a minimum of 200 cases in the experimental group and 200 in the control group) was not met or if the optimal information size was met but the 95% CI of the mean difference crossed zero. Assessment of publication bias was conducted by a visual assessment of symmetry of the funnel plot. Publication bias was quantitatively assessed using Egger and Begg tests, using SPSS statistical software version 23 (IBM).40,41P < .10 was considered evidence of publication bias.

    Data Synthesis and Analysis

    Results were synthesized using a quantitative DerSimonian and Laird meta-analysis using Review Manager 5.3 (Cochrane).42 A fixed- or random-effects model was used according to heterogeneity, and thus a fixed-effects model was used. An overall absolute change in LBM in kilograms was reported for each treatment arm. Statistical significance was determined at a level of .05 (2-tailed). A summary mean difference in LBM (with 95% CIs) and I2 statistic were presented for each meta-analysis.

    Subgroup Analyses

    Hormone therapy dosage was examined separately within estrogen-only and estrogen-progesterone treatment arms. The various estrogen types used in HT are not equivalent; therefore, all estrogen dosages were standardized using reference values (eTable 2 in the Supplement).43-45 All values were standardized to those of conjugated equine estrogens, the most commonly used estrogen type across the included studies. Estrogen-only and estrogen-progesterone arms were stratified by an estrogen dose of 0.625 mg or greater (standard dosage or higher) or less than 0.625 mg (low dosage). The proposed mechanism of action for HT on muscle maintenance is through estrogen. Therefore, the estrogen-progesterone treatment arms were not stratified by progesterone dosage.

    Follow-up duration subgroups were categorized as longer (>2 years) or shorter (≤2 years). These thresholds were selected because they most evenly dichotomized the study and participant types and captured the range of follow-up duration. Follow-up duration was used as a proxy for total duration of HT because the reported follow-up durations were similar or the same as the duration of HT use across most studies.46-53 It is crucial to explore the variability in the duration of estrogen treatment because prolonged exposure to estrogen may be required to pose benefits for LBM preservation. Menopausal age was characterized based on the time since menopausal onset of study participants. Studies with participants with menopausal onset within the past 10 years were included. Generally, it is recommended for postmenopausal women to begin HT use nearer to menopause, specifically within the first 10 years.54,55 Time-since-menopause subgroups were also categorized as shorter (<5 years) or longer (≥5 years).

    Study quality subgroups were categorized by fair or good quality vs poor quality. Lean body mass measurement type subgroups were categorized as DEXA or other. Dual-energy x-ray absorptiometry is considered the criterion standard of body composition measurement; therefore, all other types were combined and compared against it.56

    Results
    Literature Flow

    Among the 21 studies, which included 4474 participants, the mean (SD) age was 59.0 (6.1) years. Data on ethnicity were presented in 2 of the 21 studies. The electronic search of the literature yielded 8961 potentially relevant articles, leaving 219 after the screening of titles and abstracts and 21 articles after full-text screening. Two studies were excluded owing to the method of muscle measurement (skin fold thickness and muscle cross-sectional area), and 1 was excluded because its cohort overlapped with that of another included study. Both of these studies used data from the WHI trials, and the study with the longest duration of follow-up data was used in the analyses.46,57 Furthermore, the excluded WHI study did not have the require data for pooling.57 Four studies were excluded because they provided qualitative descriptions of changes in LBM and did not have numeric data available for pooling. Two more studies were excluded because they did not have data available for pooling. Twelve studies46-53,58-61 remained and were included in the analysis (Figure 1).

    Study Characteristics

    Overall, 6 studies were from the United States and 6 were conducted in Europe. The total number of recruited participants across all 12 applicable studies was 4474, and the median duration of follow-up for studies was 2 years (range, 6 months to 6 years). The age of participants ranged from 45 to 75 years (Table 1).62 The full study characteristics are presented in eTables 3 through 5 in the Supplement. The studies had a total of 22 HT treatment arms, 15 of which used estrogen-progesterone combination HT and 7 of which used estrogen-only HT. Treatment duration ranged from 9 to 25 days per month to more than 8 years and varied in dosage. Control participants received either no HT at all or placebo. Eighteen treatment arms consisted of continuous dosage, and 4 used a cyclical dosage regimen. The treatment arms of the included studies depicted varied impacts of the HT, with 7 arms associated with a loss of LBM over the treatment period and 14 arms associated with LBM retention. (Table 2). For the meta-analyses, 21 treatment arms were considered, because the study by Jensen et al49 presented results with the 2 HT treatment arms combined. In addition, there were discrepancies between sample sizes in the treatment and control arms for many of the studies. This may indicate fault in randomization or loss to follow-up.

    Risk of Bias of Included Studies

    Six of the 12 studies (50%) were at high risk of bias, 4 (33%) were unclear, and 2 (17%) were at low risk of bias (Table 2; eTable 6 in the Supplement). Mainly, the studies showed reporting deficiencies, where information was not explicitly stated.

    Meta-analyses
    Main Effect Analysis

    Across all studies, participants receiving HT lost 0.06 kg less LBM (95% CI, −0.05 to 0.18; I2 = 0%) compared with those not receiving HT (Figure 2). These findings do not present a statistically significant change in LBM in women receiving HT (P = .26).

    Subgroup Analyses

    The studies were stratified and analyzed by the following subgroups: HT type and dosage, duration of follow-up, time since menopause, study quality, and type of LBM measurement. The studies were stratified and analyzed by the following subgroups: HT type and dosage (HT users lost 0.06 kg more to 0.19 kg less LBM than nonusers), duration of follow-up (HT users lost 0.0 to 0.10 kg less LBM than nonusers), time since menopause (HT users lost 0.01 to 0.13 kg less LBM than nonusers), study quality (HT users lost 0.04 to 0.20 kg less LBM than nonusers), and type of LBM measurement (HT users lost 0.06 to 0.07 kg less LBM than nonusers). There were no significant differences in LBM change between women receiving HT and not receiving HT for any group (eTables 7-19 in the Supplement).

    Publication Bias

    A visual inspection of the funnel plot of effect size and precision presents asymmetry, indicating potential publication bias (eFigure in the Supplement). The Egger and Begg tests also suggest publication bias (Egger P = .02; Begg P = .04).

    GRADE Assessment

    Based on GRADE, the overall quality of evidence was low. In the subgroup analyses, estrogen-progesterone treatment arms with estrogen dosage of 0.625 mg or greater, studies with longer follow-up, shorter and longer time since menopause, poor quality, and other LBM measurement types had low quality of evidence. Subgroups with estrogen-only treatment arms of any dosage, estrogen-progesterone treatment arms with estrogen dosage less than 0.625 mg, shorter follow-up duration, good quality, and DEXA measurement had moderate quality of evidence. Imprecision was a problem for almost all subgroups, and risk of bias was a problem for most. The GRADE assessment of the quality of evidence is presented in eTable 20 in the Supplement.

    Discussion

    This systematic review and meta-analyses evaluated 12 randomized clinical trials exploring the role of estrogen-based HT on muscle mass. Overall, HT users lost 0.06 kg (–0.05 to 0.18) less LBM compared with participants not receiving HT. This finding was not statistically significant and is unlikely to be clinically relevant for the average postmenopausal woman. It is reported that women older than 50 years lose approximately 1% of muscle mass annually.63,64 At this rate, it would take approximately 66 years for a woman of average height and LBM65,66 to become sarcopenic according to the cutoff of 7.4 kg/m2 recommended by the European Working Group on Sarcopenia.67 Based on the results of this meta-analysis, HT use could increase the amount of sarcopenia-free time to almost 80 years. However, most women would not live long enough to experience these additional sarcopenia-free years. The small potential benefit for maintaining muscle mass in the general population of postmenopausal women likely does not outweigh the potential risks of prolonged HT.18 Also, sarcopenia in postmenopausal women is associated most with physical inactivity, reduced protein intake, and oxidative stress occurring at the time of menopause,68 but not directly with menopause itself. It is possible this is why HT does not appear to offer any benefit to retaining muscle after menopause, despite the decline in muscle mass during this time.

    Hormone therapy could be beneficial to women with a lower muscle mass at baseline; however, to our knowledge, no research in this specific population has been conducted. It has also been hypothesized that HT could be effective in maintaining muscle mass when combined with exercise therapy. However, studies have found that although resistance exercise has a statistically significant association with protection of muscle mass,69,70 the combination of exercise and HT does not offer any significant benefit for muscle mass maintenance compared with exercise alone.14,61,71

    This systematic review and meta-analysis improves on limitations of the existing literature by limiting the scope to HT use and muscle mass. We have provided a comprehensive summary of the available literature on this topic and conducted various subgroup analyses to determine whether the association of HT with LBM users differed based on the estrogen dose, whether progesterone was included, duration of follow-up, time since menopause, method of measuring muscle mass, and study quality. Across all subgroups, women receiving HT lost between 0.06 kg more muscle mass to 0.20 kg less muscle mass compared with the control groups, although none of these subgroup analyses were statistically significant.

    Limitations of this review include not being able to explore subgroups such as dosage regimens (cyclical vs continuous), patient characteristics (ie, ethnicity), or amount of physical activity. In this analysis, 4 treatment arms reported using a cyclical dosage regimen and of these, 2 did not report follow-up duration. Most of the included studies did not report ethnicity or amount of exercise. Owing to these factors, we were unable to perform these subgroup analyses. Although we believe it is unlikely for future studies to find an association between HT use and attenuation of LBM loss in postmenopausal women, studies could improve on the current literature by providing data on these subgroups as well as using longer follow-up. Studies may also consider focusing on women with lower LBM at baseline to evaluate the potential benefit in a higher-risk population. In addition, our analysis exploring the window of opportunity for HT less than 10 years after menopausal onset was limited because the studies were not designed to include women in very early menopause. Our follow-up duration subgroup analysis was also limited because we used follow-up duration as a proxy measure for total duration of HT use, as some studies did not explicitly report the latter.49,58,60,61

    Further work is also required to determine whether HT is beneficial to muscle strength or function. Muscle strength is more important to health outcomes than muscle mass72; however, we are not aware of any biological link between HT and muscle strength that would not be mediated through muscle mass, hence the reason this analysis focused on the latter. A previous systematic review and meta-analysis of 23 human studies has shown small, significant benefits of HT in preserving skeletal muscle strength, translating to approximately 5% greater strength in HT users compared with control participants.31 However, the type, dosage, and duration of HT among these studies were not consistent and varied greatly from study to study. Therefore, further work in this area is required.

    Limitations

    This study had several limitations. Many of the studies used in our review were considered to have a high risk of bias and the overall quality of evidence was low based on GRADE. The quality of evidence was commonly downgraded owing to study risk of bias, publication bias, or imprecision. Imprecision was present when studies did not meet the optimal information size or if the 95% CI of the mean difference crossed zero. However, this definition of imprecision is difficult to interpret if we assume that there is a null association and that the CI should include zero. In addition, the presence of publication bias shows that smaller studies with larger, significant effects are more likely to be published. In a meta-analysis, this can skew results in favor of the treatment, whether or not a true effect exists. Despite the literature’s limitations, the results of this review remained consistent across subgroups, indicating that the overall body of literature has not shown a meaningful association between HT and muscle mass. Of the 12 included studies, 1 had a statistically significant result; however, it was severely limited by a sample size of 14 participants.

    Conclusions

    This systematic review and meta-analysis of 12 randomized clinical trials exploring muscle mass retention in postmenopausal women did not show a significant beneficial or detrimental association of HT with muscle mass. Pooling data across all studies, participants using HT lost 0.06 kg (95% CI, –0.05 to 0.18 kg; P = .26) less LBM compared with the control participants, and significant between study heterogeneity remained. Individual study effects ranged from –0.06 kg (–0.30 to 0.19 kg) to 0.20 kg (–0.08 to 0.48 kg). Findings from subgroup analyses by follow-up duration, time since menopause, study quality, estrogen dosage, and LBM measurement type were not statistically significant. Despite the limitations of the literature, this study highlights the consistently null results in studies investigating HT and retention of muscle mass. The importance of muscle retention in aging women is crucial, but these findings suggest that interventions other than HT should be explored.

    Back to top
    Article Information

    Accepted for Publication: July 8, 2019.

    Published: August 28, 2019. doi:10.1001/jamanetworkopen.2019.10154

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Javed AA et al. JAMA Network Open.

    Corresponding Author: Parminder Raina, PhD, Department of Health Research Methods, Evidence, and Impact at McMaster University, McMaster Innovation Park, Ste 309A, 175 Longwood Rd S, Hamilton, ON L8P 0A1, Canada (praina@mcmaster.ca).

    Author Contributions: Dr Raina had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Javed, Mayhew, Raina.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Javed, Raina.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Javed, Mayhew, Raina.

    Administrative, technical, or material support: Shea.

    Supervision: Mayhew, Raina.

    Conflict of Interest Disclosures: Dr Raina holds a Tier 1 Canada Research Chair in Geroscience and the Raymond and Margaret Labarge Chair in Research and Knowledge Application for Optimal Aging. No other disclosures were reported.

    References
    1.
    World Health Organization. Ageing and health. https://www.who.int/ageing/publications/global_health.pdf?ua. Published 2018. Acccessed May 25, 2018.
    2.
    Austad  SN.  Why women live longer than men: sex differences in longevity.  Gend Med. 2006;3(2):79-92. doi:10.1016/S1550-8579(06)80198-1PubMedGoogle Scholar
    3.
    Kirchengast  S, Huber  J.  Gender and age differences in lean soft tissue mass and sarcopenia among healthy elderly.  Anthropol Anz. 2009;67(2):139-151. doi:10.1127/0003-5548/2009/0018PubMedGoogle Scholar
    4.
    Shafiee  G, Keshtkar  A, Soltani  A, Ahadi  Z, Larijani  B, Heshmat  R.  Prevalence of sarcopenia in the world: a systematic review and meta-analysis of general population studies.  J Diabetes Metab Disord. 2017;16(1):21. doi:10.1186/s40200-017-0302-xPubMedGoogle Scholar
    5.
    Takahashi  TA, Johnson  KM.  Menopause.  Med Clin North Am. 2015;99(3):521-534. doi:10.1016/j.mcna.2015.01.006PubMedGoogle Scholar
    6.
    Janssen  I, Heymsfield  SB, Ross  R.  Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability.  J Am Geriatr Soc. 2002;50(5):889-896. doi:10.1046/j.1532-5415.2002.50216.xPubMedGoogle Scholar
    7.
    Scott  D, Hayes  A, Sanders  KM, Aitken  D, Ebeling  PR, Jones  G.  Operational definitions of sarcopenia and their associations with 5-year changes in falls risk in community-dwelling middle-aged and older adults.  Osteoporos Int. 2014;25(1):187-193. doi:10.1007/s00198-013-2431-5PubMedGoogle Scholar
    8.
    Landi  F, Liperoti  R, Russo  A,  et al.  Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study.  Clin Nutr. 2012;31(5):652-658. doi:10.1016/j.clnu.2012.02.007PubMedGoogle Scholar
    9.
    Tanimoto  Y, Watanabe  M, Sun  W,  et al.  Sarcopenia and falls in community-dwelling elderly subjects in Japan: defining sarcopenia according to criteria of the European Working Group on Sarcopenia in Older People.  Arch Gerontol Geriatr. 2014;59(2):295-299. doi:10.1016/j.archger.2014.04.016PubMedGoogle Scholar
    10.
    Gariballa  S, Alessa  A.  Sarcopenia: prevalence and prognostic significance in hospitalized patients.  Clin Nutr. 2013;32(5):772-776. doi:10.1016/j.clnu.2013.01.010PubMedGoogle Scholar
    11.
    Kim  JH, Lim  S, Choi  SH,  et al.  Sarcopenia: an independent predictor of mortality in community-dwelling older Korean men.  J Gerontol A Biol Sci Med Sci. 2014;69(10):1244-1252. doi:10.1093/gerona/glu050PubMedGoogle Scholar
    12.
    Landi  F, Cruz-Jentoft  AJ, Liperoti  R,  et al.  Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study.  Age Ageing. 2013;42(2):203-209. doi:10.1093/ageing/afs194PubMedGoogle Scholar
    13.
    Tankó  LB, Movsesyan  L, Svendsen  OL, Christiansen  C.  The effect of hormone replacement therapy on appendicular lean tissue mass in early postmenopausal women.  Menopause. 2002;9(2):117-121. doi:10.1097/00042192-200203000-00006PubMedGoogle Scholar
    14.
    Brown  M, Birge  SJ, Kohrt  WM.  Hormone replacement therapy does not augment gains in muscle strength or fat-free mass in response to weight-bearing exercise.  J Gerontol A Biol Sci Med Sci. 1997;52(3):B166-B170. doi:10.1093/gerona/52A.3.B166PubMedGoogle Scholar
    15.
    Dayal  M, Sammel  MD, Zhao  J, Hummel  AC, Vandenbourne  K, Barnhart  KT.  Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids.  J Womens Health (Larchmt). 2005;14(5):391-400. doi:10.1089/jwh.2005.14.391PubMedGoogle Scholar
    16.
    Dobs  AS, Nguyen  T, Pace  C, Roberts  CP; AS D.  Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women.  J Clin Endocrinol Metab. 2002;87(4):1509-1516. doi:10.1210/jcem.87.4.8362PubMedGoogle Scholar
    17.
    Greeves  JP, Cable  NT, Reilly  T, Kingsland  C.  Changes in muscle strength in women following the menopause: a longitudinal assessment of the efficacy of hormone replacement therapy.  Clin Sci (Lond). 1999;97(1):79-84. doi:10.1042/cs0970079PubMedGoogle Scholar
    18.
    North American Menopause Society. The experts do agree about hormone therapy. http://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/the-experts-do-agree-about-hormone-therapy. Published 2019. Accessed July 23, 2019.
    19.
    Bemben  DA, Langdon  DB.  Relationship between estrogen use and musculoskeletal function in postmenopausal women.  Maturitas. 2002;42(2):119-127. doi:10.1016/S0378-5122(02)00033-6PubMedGoogle Scholar
    20.
    Taaffe  DR, Newman  AB, Haggerty  CL,  et al.  Estrogen replacement, muscle composition, and physical function: The Health ABC Study.  Med Sci Sports Exerc. 2005;37(10):1741-1747. doi:10.1249/01.mss.0000181678.28092.31PubMedGoogle Scholar
    21.
    Lemoine  S, Granier  P, Tiffoche  C, Rannou-Bekono  F, Thieulant  ML, Delamarche  P.  Estrogen receptor alpha mRNA in human skeletal muscles.  Med Sci Sports Exerc. 2003;35(3):439-443. doi:10.1249/01.MSS.0000053654.14410.78PubMedGoogle Scholar
    22.
    Dubé  JY, Lesage  R, Tremblay  RR.  Androgen and estrogen binding in rat skeletal and perineal muscles.  Can J Biochem. 1976;54(1):50-55. doi:10.1139/o76-008PubMedGoogle Scholar
    23.
    VanBrocklin  HF, Pomper  MG, Carlson  KE, Welch  MJ, Katzenellenbogen  JA.  Preparation and evaluation of 17-ethynyl-substituted 16 α-[18F]fluoroestradiols: selective receptor-based PET imaging agents.  Int J Rad Appl Instrum B. 1992;19(3):363-374. doi:10.1016/0883-2897(92)90122-FPubMedGoogle Scholar
    24.
    Friend  KE, Hartman  ML, Pezzoli  SS, Clasey  JL, Thorner  MO.  Both oral and transdermal estrogen increase growth hormone release in postmenopausal women—a clinical research center study.  J Clin Endocrinol Metab. 1996;81(6):2250-2256.PubMedGoogle Scholar
    25.
    Dionne  IJ, Kinaman  KA, Poehlman  ET.  Sarcopenia and muscle function during menopause and hormone-replacement therapy.  J Nutr Health Aging. 2000;4(3):156-161.PubMedGoogle Scholar
    26.
    D’Eon  T, Braun  B.  The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise.  J Womens Health Gend Based Med. 2002;11(3):225-237. doi:10.1089/152460902753668439PubMedGoogle Scholar
    27.
    Rossouw  JE, Anderson  GL, Prentice  RL,  et al; Writing Group for the Women’s Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.  JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321PubMedGoogle Scholar
    28.
    Hodis  HN, Mack  WJA.  A “window of opportunity”: the reduction of coronary heart disease and total mortality with menopausal therapies is age- and time-dependent.  Brain Res. 2011;1379:244-252. doi:10.1016/j.brainres.2010.10.076PubMedGoogle Scholar
    29.
    Hodis  HN, Collins  P, Mack  WJ, Schierbeck  LL.  The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective.  Climacteric. 2012;15(3):217-228. doi:10.3109/13697137.2012.656401PubMedGoogle Scholar
    30.
    Sipilä  S, Poutamo  J.  Muscle performance, sex hormones and training in peri-menopausal and post-menopausal women.  Scand J Med Sci Sports. 2003;13(1):19-25. doi:10.1034/j.1600-0838.2003.20210.xPubMedGoogle Scholar
    31.
    Greising  SM, Baltgalvis  KA, Lowe  DA, Warren  GL.  Hormone therapy and skeletal muscle strength: a meta-analysis.  J Gerontol A Biol Sci Med Sci. 2009;64(10):1071-1081. doi:10.1093/gerona/glp082PubMedGoogle Scholar
    32.
    Tiidus  PM.  Benefits of estrogen replacement for skeletal muscle mass and function in post-menopausal females: evidence from human and animal studies.  Eurasian J Med. 2011;43(2):109-114. doi:10.5152/eajm.2011.24PubMedGoogle Scholar
    33.
    Gambacciani  M, Ciaponi  M, Cappagli  B, De Simone  L, Orlandi  R, Genazzani  AR.  Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.  Maturitas. 2001;39(2):125-132. doi:10.1016/S0378-5122(01)00194-3PubMedGoogle Scholar
    34.
    Baumgartner  RN, Waters  DL, Gallagher  D, Morley  JE, Garry  PJ.  Predictors of skeletal muscle mass in elderly men and women.  Mech Ageing Dev. 1999;107(2):123-136. doi:10.1016/S0047-6374(98)00130-4PubMedGoogle Scholar
    35.
    Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  PLoS Med. 2009;6(7):e1000100. doi:10.1371/journal.pmed.1000100PubMedGoogle Scholar
    36.
    Evidence Partners. DistillerSR: better, faster systematic reviews used systematic review software. https://www.evidencepartners.com/products/distillersr-systematic-review-software/. Published 2011. Accessed April 25, 2018.
    37.
    Higgins  JPT, Altman  DG, Gøtzsche  PC,  et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.  BMJ. 2011;343(7829):d5928. doi:10.1136/bmj.d5928PubMedGoogle Scholar
    38.
    Guyatt  G, Oxman  AD, Akl  EA,  et al.  GRADE guidelines: 1, introduction-GRADE evidence profiles and summary of findings tables.  J Clin Epidemiol. 2011;64(4):383-394. doi:10.1016/j.jclinepi.2010.04.026PubMedGoogle Scholar
    39.
    Guyatt  GH, Oxman  AD, Vist  GE,  et al; GRADE Working Group.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.  BMJ. 2008;336(7650):924-926. doi:10.1136/bmj.39489.470347.ADPubMedGoogle Scholar
    40.
    Stuck  AE, Rubenstein  LZ, Wieland  D.  Bias in meta-analysis detected by a simple, graphical test: asymmetry detected in funnel plot was probably due to true heterogeneity.  BMJ. 1998;316(7129):469-471. doi:10.1136/bmj.316.7129.469PubMedGoogle Scholar
    41.
    Begg  CB, Mazumdar  M.  Operating characteristics of a rank correlation test for publication bias.  Biometrics. 1994;50(4):1088-1101. doi:10.2307/2533446PubMedGoogle Scholar
    42.
    Review Manager (RevMan) [computer program]. Version 5.3. Copenhagen, Denmark: Nordic Cochrane Centre, Cochrane Collaboration; 2014.
    43.
    Gambacciani  M, Genazzani  AR.  Hormone replacement therapy: the benefits in tailoring the regimen and dose.  Maturitas. 2001;40(3):195-201. doi:10.1016/S0378-5122(01)00281-XPubMedGoogle Scholar
    44.
    Lindsay  R, Hart  DM, Clark  DM.  The minimum effective dose of estrogen for prevention of postmenopausal bone loss.  Obstet Gynecol. 1984;63(6):759-763.PubMedGoogle Scholar
    45.
    Panay  N, Ylikorkala  O, Archer  DF, Gut  R, Lang  E.  Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief.  Climacteric. 2007;10(2):120-131. doi:10.1080/13697130701298107PubMedGoogle Scholar
    46.
    Bea  JW, Zhao  Q, Cauley  JA,  et al.  Effect of hormone therapy on lean body mass, falls, and fractures: 6-year results from the Women’s Health Initiative hormone trials.  Menopause. 2011;18(1):44-52. doi:10.1097/gme.0b013e3181e3aab1PubMedGoogle Scholar
    47.
    Blackman  MR, Sorkin  JD, Münzer  T,  et al.  Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial.  JAMA. 2002;288(18):2282-2292. doi:10.1001/jama.288.18.2282PubMedGoogle Scholar
    48.
    Haarbo  J, Marslew  U, Gotfredsen  A, Christiansen  C.  Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause.  Metabolism. 1991;40(12):1323-1326. doi:10.1016/0026-0495(91)90037-WPubMedGoogle Scholar
    49.
    Jensen  LB, Vestergaard  P, Hermann  AP,  et al.  Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study.  J Bone Miner Res. 2003;18(2):333-342. doi:10.1359/jbmr.2003.18.2.333PubMedGoogle Scholar
    50.
    Kenny  AM, Kleppinger  A, Wang  Y, Prestwood  KM.  Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women.  J Am Geriatr Soc. 2005;53(11):1973-1977. doi:10.1111/j.1532-5415.2005.53567.xPubMedGoogle Scholar
    51.
    Pöllänen  E, Ronkainen  PH, Suominen  H,  et al.  Muscular transcriptome in postmenopausal women with or without hormone replacement.  Rejuvenation Res. 2007;10(4):485-500. doi:10.1089/rej.2007.0536PubMedGoogle Scholar
    52.
    Sipilä  S, Taaffe  DR, Cheng  S, Puolakka  J, Toivanen  J, Suominen  H.  Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: a randomized placebo-controlled study.  Clin Sci (Lond). 2001;101(2):147-157. doi:10.1042/cs1010147PubMedGoogle Scholar
    53.
    Thorneycroft  IH, Lindsay  R, Pickar  JH.  Body composition during treatment with conjugated estrogens with and without medroxyprogesterone acetate: analysis of the Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial.  Am J Obstet Gynecol. 2007;197(2):137.e1-137.e7. doi:10.1016/j.ajog.2007.05.042PubMedGoogle Scholar
    54.
    de Villiers  TJ, Pines  A, Panay  N,  et al; International Menopause Society.  Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health.  Climacteric. 2013;16(3):316-337. doi:10.3109/13697137.2013.795683PubMedGoogle Scholar
    55.
    Santen  RJ, Allred  DC, Ardoin  SP,  et al; Endocrine Society.  Postmenopausal hormone therapy: an Endocrine Society scientific statement.  J Clin Endocrinol Metab. 2010;95(7)(suppl 1):s1-s66. doi:10.1210/jc.2009-2509PubMedGoogle Scholar
    56.
    Branski  LK, Norbury  WB, Herndon  DN,  et al.  Measurement of body composition in burned children: is there a gold standard?  JPEN J Parenter Enteral Nutr. 2010;34(1):55-63. doi:10.1177/0148607109336601PubMedGoogle Scholar
    57.
    Chen  Z, Bassford  T, Green  SB,  et al.  Postmenopausal hormone therapy and body composition—a substudy of the estrogen plus progestin trial of the Women’s Health Initiative.  Am J Clin Nutr. 2005;82(3):651-656. doi:10.1093/ajcn/82.3.651PubMedGoogle Scholar
    58.
    Hassager  C, Christiansen  C.  Estrogen/gestagen therapy changes soft tissue body composition in postmenopausal women.  Metabolism. 1989;38(7):662-665. doi:10.1016/0026-0495(89)90104-2PubMedGoogle Scholar
    59.
    Sørensen  MB, Rosenfalck  AM, Højgaard  L, Ottesen  B.  Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy.  Obes Res. 2001;9(10):622-626. doi:10.1038/oby.2001.81PubMedGoogle Scholar
    60.
    Aloia  JF, Vaswani  A, Russo  L, Sheehan  M, Flaster  E.  The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass.  Am J Obstet Gynecol. 1995;172(3):896-900. doi:10.1016/0002-9378(95)90018-7PubMedGoogle Scholar
    61.
    Evans  EM, Van Pelt  RE, Binder  EF, Williams  DB, Ehsani  AA, Kohrt  WM.  Effects of HRT and exercise training on insulin action, glucose tolerance, and body composition in older women.  J Appl Physiol (1985). 2001;90(6):2033-2040. doi:10.1152/jappl.2001.90.6.2033PubMedGoogle Scholar
    62.
    Washburn  RA, Smith  KW, Jette  AM, Janney  CA.  The Physical Activity Scale for the Elderly (PASE): development and evaluation.  J Clin Epidemiol. 1993;46(2):153-162. doi:10.1016/0895-4356(93)90053-4PubMedGoogle Scholar
    63.
    Goodpaster  BH, Park  SW, Harris  TB,  et al.  The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.  J Gerontol A Biol Sci Med Sci. 2006;61(10):1059-1064. doi:10.1093/gerona/61.10.1059PubMedGoogle Scholar
    64.
    von Haehling  S, Morley  JE, Anker  SD.  An overview of sarcopenia: facts and numbers on prevalence and clinical impact.  J Cachexia Sarcopenia Muscle. 2010;1(2):129-133. doi:10.1007/s13539-010-0014-2PubMedGoogle Scholar
    65.
    Bea  JW, Thomson  CA, Wertheim  BC,  et al.  Risk of mortality according to body mass index and body composition among postmenopausal women.  Am J Epidemiol. 2015;182(7):585-596. doi:10.1093/aje/kwv103PubMedGoogle Scholar
    66.
    Barhum  BL, Marcin  J. What is the average height for women? https://www.medicalnewstoday.com/articles/321132.php. Accessed April 25, 2018.
    67.
    Coraci  D, Santilli  V, Padua  L.  Comment on “Cut-off points to identify sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP) definition.”  Clin Nutr. 2016;35(6):1568-1569. doi:10.1016/j.clnu.2016.06.026PubMedGoogle Scholar
    68.
    Maltais  ML, Desroches  J, Dionne  IJ.  Changes in muscle mass and strength after menopause.  J Musculoskelet Neuronal Interact. 2009;9(4):186-197.PubMedGoogle Scholar
    69.
    Ryan  AS, Pratley  RE, Elahi  D, Goldberg  AP.  Resistive training increases fat-free mass and maintains RMR despite weight loss in postmenopausal women.  J Appl Physiol (1985). 1995;79(3):818-823. doi:10.1152/jappl.1995.79.3.818PubMedGoogle Scholar
    70.
    Goulet  ED, Mélançon  MO, Dionne  IJ, Aubertin-Leheudre  M.  No sustained effect of aerobic or resistance training on insulin sensitivity in nonobese, healthy older women.  J Aging Phys Act. 2005;13(3):314-326. doi:10.1123/japa.13.3.314PubMedGoogle Scholar
    71.
    Figueroa  A, Going  SB, Milliken  LA,  et al.  Effects of exercise training and hormone replacement therapy on lean and fat mass in postmenopausal women.  J Gerontol A Biol Sci Med Sci. 2003;58(3):266-270. doi:10.1093/gerona/58.3.M266PubMedGoogle Scholar
    72.
    Newman  AB, Kupelian  V, Visser  M,  et al.  Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort.  J Gerontol A Biol Sci Med Sci. 2006;61(1):72-77. doi:10.1093/gerona/61.1.72PubMedGoogle Scholar
    ×