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Summary

Estrogen, mediated by both genomic and non-genomic pathways, contributes to the preservation of muscle mass and strength via effects on mitochondrial function, satellite cell regeneration, apoptosis, protein turnover, inflammation and myosin binding [1]. Earlier age at natural menopause is associated with reduced physical function parameters [2]. Although bone loss and osteoporosis are well recognised and feared consequences of premature ovarian insufficiency (POI) [3], data regarding muscle is lacking [1]; with previous investigations in women with POI showing conflicting results. The recent cross-sectional study by Li and co-workers [4] helps to address this knowledge gap by demonstrating in Chinese women with spontaneous POI (n=59) a greater prevalence of decreased muscle mass as well as lower appendicular skeletal muscle mass (ASM) and total skeletal muscle mass (TSMM), which was independent of age, body mass index (BMI) and lifestyle factors as compared with premenopausal controls (n=57).

Commentary

The present commented study is the first to investigate the muscle health in Chinese women with POI. According to the investigators POI women had lower muscle mass and a higher prevalence of low muscle mass as compared to healthy controls. A study of Danish women with Turner syndrome (TS), a genetic cause of POI, reported reduced muscle mass, oxygen uptake, and physical activity versus premenopausal controls [5]. Lower ASM was observed in women with spontaneous or iatrogenic POI versus controls [6]. In contrast, a study of Brazilian women with normal karyotype spontaneous POI, showed no difference in ASM versus controls [7].

Sarcopenia, defined as loss of muscle mass, strength and function, is recognised as a significant contributor to increased morbidity and mortality in aging women [8,9]. However, a lack of consensus regarding definitions and diagnostic criteria for sarcopenia is reflected in the varying reported prevalence ranging from 2-27% [9,10]. There is increasing recognition of the bi-directional relationship between muscle and bone, mediated by osteokines and myokines [1], leading to the concept of ‘osteosarcopenia’, where osteoporosis/penia and sarcopenia co-exist [8,11]. Lower muscle mass and function is associated with bone microarchitecture abnormalities, decreased bone size and bending strength [11]. As used in the current study [4], the Asian Working Group for Sarcopenia definition includes: low muscle mass <5.4 kg.m2 (dual x-ray absorptiometry (DXA)-derived ASM) and reduced grip strength (<18 kg). Unfortunately, no measurement of muscle strength was performed and bone density findings are not provided [4]. However, one-third of POI participants in this study could be considered “pre-sarcopenic” or “sarcopenic” depending on normal or reduced muscle strength respectively. Current POI guidelines recommend DXA to assess fracture risk [3]. Despite limitations [1,9], DXA-derived ASM (as reported here [4]) combined with grip strength/ gait speed could potentially provide useful sarcopenia screening information [8,9] in women with POI.

Meta-analyses indicate a positive effect in postmenopausal women of hormone therapy (HT) on muscle strength but not lean body mass (potentially reflecting variable study methodology, HT regimens, time since menopause or prior HT) [12,13]. Although estrogen is important in maintaining bone density in women with POI [6,14,15], data is inconclusive regarding muscle parameters and HT exposure [1]. A five year randomised trial reported increased lean mass in TS women taking high dose 4 mg estradiol but not 2 mg estradiol per day [14]. Longitudinal analysis (median 6 year follow-up) indicated that continued estrogen HT was associated with a significant increase in ASM compared to baseline [6]. No difference was observed between HT users and non-users in the current commented study [4], potentially reflecting sample size limitations.

Despite a lack of consensus regarding optimal management of osteosarcopenia, progressive resistance and balance exercise, nutritional supplementation and anti-resorptive therapies are proposed therapeutic options [8,9]. However, data related to women with POI is lacking and research is needed. This study highlights the question of whether women with POI are at risk of sarcopenia/ osteosarcopenia, indicating the need for increased awareness, further research, and consideration of interventions to optimise muscle, as well as bone health, in women with POI.

Amanda Vincent, MBBS, B Med Sci (Hons), PhD, FRACP
Head, Early Menopause research, Monash Centre for Health Research and Implementation (MCHRI), School of Public Health and Preventive Medicine, Monash University; Endocrinologist, Department of Endocrinology, Monash Health, Clayton, Victoria, Australia; Board member of the International Menopause Society

References

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    https://pubmed.ncbi.nlm.nih.gov/33418593/
  2. Cho H, Gu MS, Won CW, Kong HH. Impact of premature natural menopause on body composition and physical function in elderly women: A Korean frailty and aging cohort study. Medicine (Baltimore). 2021;100(25):e26353.
    https://pubmed.ncbi.nlm.nih.gov/34160403/
  3. Panay N, Anderson RA, Nappi RE, et al. Premature ovarian insufficiency: an International Menopause Society White Paper. Climacteric. 2020;23(5):426-446.
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  5. Gravholt CH, Hjerrild BE, Mosekilde L, et al. Body composition is distinctly altered in Turner syndrome: relations to glucose metabolism, circulating adipokines, and endothelial adhesion molecules. Eur J Endocrinol. 2006;155(4):583-592.
    https://pubmed.ncbi.nlm.nih.gov/16990658/
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    https://pubmed.ncbi.nlm.nih.gov/19561145/
  13. Javed AA, Mayhew AJ, Shea AK, Raina P. Association Between Hormone Therapy and Muscle Mass in Postmenopausal Women: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019;2(8):e1910154.
    https://pubmed.ncbi.nlm.nih.gov/31461147/
  14. Cleemann L, Holm K, Kobbernagel H, et al. Dosage of estradiol, bone and body composition in Turner syndrome: a 5-year randomized controlled clinical trial. Eur J Endocrinol. 2017;176(2):233-242
    https://pubmed.ncbi.nlm.nih.gov/27881458/
  15. Gazarra LBC, Bonacordi CL, Yela DA, Benetti-Pinto CL. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27(10):1110-1116.
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