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Introduction & Physiological Foundations

SECTION 1

1. Skeletal Muscle Disorders in Menopausal Women

​2. Musculoskeletal Syndrome of Menopause (MSM)

3. Menopausal Transition & Hormonal Changes

4. Estrogen Receptor Signaling in Muscle Tissue 

Clinical Takeaways

  • Screen muscle strength in midlife women. 

  • Educate patients about MSM. 

  • Encourage resistance training and physical activity. 

  • Consider hormone therapy when appropriate. 

Key Concepts​​

Clinical Relevance​​

  • Sarcopenia: Age-related loss of skeletal muscle mass.

  • ​Dynapenia: Age-related decline in muscle strength, independent of muscle mass loss. ​

  • Dynapenia is a stronger predictor of falls, disability, and mortality than sarcopenia.

  • Strength loss occurs 2–5 times faster than muscle mass loss during aging.

  • Clinical assessments should prioritize muscle function and quality, not just mass. 

Definition

A constellation of musculoskeletal symptoms linked to estrogen deficiency during the

menopausal transition. 

Common Features

  • Joint pain (arthralgia)

  • Accelerated osteoarthritis

  • Bone density loss

  • Muscle mass and strength decline

Prevalence

  • Affects >70% of women during perimenopause to postmenopause. 

  • Up to 25% may experience disabling symptoms. 

Physiology

  • Menopause is defined retrospectively after 12 months of amenorrhea. 

  • The menopausal transition (MT) involves fluctuating and ultimately declining estradiol (Eâ‚‚) levels.

Impact on Muscle

  • Eâ‚‚ is critical for muscle mass maintenance and muscle quality. 

  • Declining Eâ‚‚ contributes to reduced muscle regeneration, impaired mitochondrial function, and increased risk of sarcopenia and dynapenia. 

Mechanism

  • Skeletal muscles express estrogen receptors (ERα) and estrogen-related receptors (ERRα, β, γ). 

  • These receptors regulate muscle growth, repair, energy metabolism, and mitochondrial function. 

Molecular Mechanisms of Estrogen-Mediated Muscle Homeostasis

SECTION 2

1. Estrogen’s Role in Muscle Protein Turnover and Anabolic Signaling

​2. Estrogen and Muscle Cell Survival & Regeneration

3. Estrogen and Mitochondrial Health

Clinical Takeaways

  • Dynapenia is more rapid and clinically significant than sarcopenia. 

  • Estrogen supports muscle health via anabolic signaling, cell survival, and mitochondrial function. 

  • Therapeutic strategies should restore hormonal balance and promote exercise and metabolic health

  • Estrogen enhances muscle responsiveness to anabolic stimuli, especially resistance exercise. 

  • Estrogen replacement therapy (ERT) improves muscle protein synthesis post-exercise. 

  • Estrogen modulates IGF-1 signaling and collagen synthesis. 

  • Estrogen deficiency increases apoptosis and impairs satellite cell function. 

  • Eâ‚‚ regulates microRNA pathways that suppress cell death signals. 

  • Estrogen supports mitochondrial DNA replication and mitophagy. 

  • Eâ‚‚ deficiency leads to oxidative stress and muscle insulin resistance.

Incidence and Prevalence Across the Female Lifespan

SECTION 3

1. Muscle Disorder Burden Across Menopausal Stages

​2. Postmenopausal Sarcopenia and Dynapenia Trends

3. Long-Term Hormone Therapy and Muscle Outcomes 

Clinical Takeaways

  • MSP is a red flag for hypoestrogenic myopathy. 

  • Monitor strength and mobility annually. 

  • Use estradiol levels to guide treatment planning. 

  • Sarcopenia prevalence: ~5.5% in premenopausal women. 

  • Musculoskeletal Pain (MSP) affects up to 71% of perimenopausal women. 

  • MSP is an early indicator of estrogen deficiency. 

  • Lean mass loss accelerates during perimenopause. 

  • Fat mass gain doubles post-final menstrual period. 

  • Sarcopenia prevalence: 7.43% postmenopause; up to 22.6% in older untreated women. 

  • Strength declines 2.5–3% per year in older women. 

  • Long-term ERT users show similar sarcopenia prevalence to non-users. 

  • Early HT initiation may offer greater muscle protection. 

4. Estradiol Levels and Symptom Severity 

  • Lower Eâ‚‚ levels correlate with increased musculoskeletal symptoms. 

  • Serum Eâ‚‚ may serve as a biomarker for symptom burden.

Influence of Race and Ethnicity on Incidence and Presentation

SECTION 4

1. Racial/Ethnic Differences in Estrogen Levels

​2. Variation in Sarcopenia Prevalence and Symptom Reporting

3. Behavioral and Socio-Environmental Modifiers 

Clinical Takeaways

  • Tailor screening and management to racial/ethnic profiles. 

  • Encourage physical activity and monitor Vitamin D levels. 

  • Eâ‚‚ levels vary across racial/ethnic groups. 

  • Japanese-American women have higher Eâ‚‚ than White women. 

  • Sarcopenia: ~20% in non-Asian women; ~11% in Asian women. 

  • Symptom burden higher in White and Hispanic women. 

  • VMS more frequent in African-American and Hispanic women. 

  • Exercise is universally protective. 

  • Vitamin D status linked to sarcopenia risk in Black and Asian women. 

Evidence-Based Preventative Strategies

SECTION 5

Clinical Takeaways

  • Resistance training and protein intake are foundational. 

  • Early intervention is key. 

  • Consider emerging dietary strategies for enhanced outcomes. 

​Risks: Includes elevated risks of thrombosis, stroke, and estrogen-sensitive cancers, requiring careful risk assessment.

Hormone Therapy 

1. Estrogen Replacement Therapy  

  • Effectiveness: ERT provides a modest but measurable increase in muscle strength (~5%, effect size ~0.23). 

  • Synergy with Exercise: Combined with resistance training, ERT enhances fat-free mass (5.5% vs. 2.9% with exercise alone). 

​

2. Timing Hypothesis & Risk  â€‹

  • Timing: Initiating HT closer to menopause maximizes muscle preservation benefits; later use is less effective.

  • Risks: Includes elevated risks of thrombosis, stroke, and estrogen-sensitive cancers, Requiring careful risk assessment 

Clinical Management and
Treatment Options

SECTION 6

Non-Hormonal Pharmacologic Agents

  1. NK3 Receptor Antagonists (e.g.,Fezolinetant, Elinzanetant): Effective at reducing hot flashes and improving sleep/mood; indirectly supports muscle recovery by enhancing overall well-being 
     

  2. SSRIs/SNRIs, Gabapentin, Clonidine, Oxybutynin: Relieve musculoskeletal pain and VMS, facilitating patient activity and aiding muscle preservation.​​​

Advanced & Investigational Therapies

  1. SS31 (Elamipretide) 

    • Mechanism: A mitochondria-targeted tetrapeptide that binds cardiolipin, stabilizes cristae, reduces oxidative stress, and enhances bioenergetics 

    • Clinical Evidence: Phase 3 trials indicate safety and signal improvements in mitochondrial myopathy and other conditions; typical dosing is 40 mg daily subcutaneously 

  2. 5Amino1MQ 

    • Mechanism: Inhibits nicotinamide N-methyltransferase (NNMT), preserving NAD+ levels and enhancing muscle strength and endurance in aged mice. 

    • Preclinical Results: Exhibits enhanced grip strength versus exercise, with potential synergistic benefits; human clinical trials are not yet available. 50 mg capsule: Take 1 capsule by mouth 1 to 3 times daily. Do not take more than 3 capsules daily 

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