Do low estrogen and testosterone reduce muscle mitochondrial biogenesis and cause fatigue?

Decreasing levels of estrogen and testosterone, particularly during the menopausal transition, significantly impact skeletal muscle bioenergetics. Research indicates that these hormones act as primary regulators of mitochondrial health, and their decline triggers a cascade that reduces the muscle's ability to generate energy efficiently.

Clinical and effectiveness evidence

In human and animal models, the loss of sex steroid signaling is directly associated with a decline in physical performance and increased fatigability.

• Performance metrics: Research in ovariectomized models (simulating estrogen deficiency) has demonstrated a staggering 92% reduction in endurance tasks (such as grid-hanging performance) and a 30% decline in grip strength.
• Human data: Biopsies from postmenopausal women reveal significantly lower oxidative capacity compared to premenopausal women. This decline correlates strongly with the duration of estrogen deficiency, suggesting a progressive loss of metabolic efficiency over time.
• Testosterone influence: Even in women, testosterone plays a vital role. Short-term increases in testosterone exposure have been shown to enhance mitochondrial respiratory flux (specifically Complex I-linked respiration), whereas deficiency is linked to reduced muscle power and increased fatigue.

Mechanistic explanations

The connection between low hormones and fatigue is rooted in the downregulation of the PGC-1α pathway, the master regulator of mitochondrial biogenesis.

• Transcription and biogenesis: Estrogen (via ERα) and testosterone (via AR) signaling promote the expression of PGC-1α. This coactivator drives the transcription of nuclear and mitochondrial DNA required to build new mitochondria. Low signaling leads to a decrease in mitochondrial mass and reduced expression of essential proteins like ATP5B and Cox4.
• Oxidative phosphorylation (OXPHOS): With fewer and less efficient mitochondria, the muscle's capacity for oxidative phosphorylation—the most efficient way to produce ATP—is compromised. This forced shift toward less efficient glycolytic (anaerobic) pathways results in faster accumulation of metabolic byproducts and a lower "ceiling" for energy output.
• Quality control: Estrogen is also critical for mitophagy (the clearance of damaged mitochondria). Its absence leads to a pool of "leaky" mitochondria that produce more reactive oxygen species (ROS) and less ATP, further exacerbating cellular fatigue.

Bottom line

The claim is strongly supported by scientific evidence. Low estrogen and testosterone signaling reduce mitochondrial biogenesis and oxidative capacity by downregulating the PGC-1α pathway, directly leading to decreased ATP production and increased physical fatigue. This mechanism explains the significant drop in endurance and muscle strength often seen during hormonal transitions.