Do low estradiol and low free testosterone reduce mitochondrial biogenesis, muscle energetics, and metabolic flexibility in postmenopausal women?

The postmenopausal decline in ovarian hormones significantly alters skeletal muscle physiology, driven by distinct cellular and metabolic changes.

Estradiol deficiency and mitochondrial function

• Biogenesis and Energetics: Low estradiol downregulates the master regulator PGC-1α, alongside downstream transcription factors TFAM and NRF-1/2, via ERα and ERβ signaling. This reduces mitochondrial content, absolute oxygen consumption, and ATP synthesis.
• Metabolic Flexibility: Estrogen-deficient muscle displays an impaired ability to utilize fatty acids, causing a shift toward glycolytic ATP production and lactate accumulation. Estradiol replacement therapy reverses these deficits, restoring respiratory chain complex activity and lipid-handling gene networks to support flexible fuel switching during exercise.

Testosterone decline and cellular energetics

• Biogenesis Pathway: Androgen receptor activation by free testosterone directly upregulates PGC-1α, NRF-1/2, and TFAM. Age-related decline in free testosterone reduces these biogenesis markers, leading to compromised mitochondrial quality control.
• Energetics and Fuel Utilization: In studies of younger women and animal models, physiological testosterone directly enhances mitochondrial respiratory capacity and oxidative function. Insufficient androgen receptor signaling in skeletal muscle impairs both glucose and fatty-acid utilization, leading to compromised ATP production and reduced fuel-switching capacity.

Bottom line

• Low estradiol directly impairs mitochondrial biogenesis, ATP production, and metabolic flexibility in postmenopausal women—deficits largely reversible with estradiol replacement. Low free testosterone similarly compromises mitochondrial biogenesis pathways, with highly plausible parallel negative impacts on muscle energetics and fuel utilization.