Do low total and free testosterone in postmenopausal women reflect reduced androgen reserve and weaker androgen signaling?

During menopause and aging, women experience a gradual decline in circulating total and free testosterone, representing a depleted circulating androgen pool.

Clinical evidence

• While low testosterone levels reflect a diminished circulating pool, "androgen reserve" or "androgen deficiency" is not a formally recognized clinical diagnosis. Major international guidelines strongly discourage using specific testosterone thresholds to diagnose deficiency, instead recommending that testosterone therapy be guided strictly by clinical symptoms of hypoactive sexual desire disorder (HSDD).
• Clinical trials of androgen receptor (AR)-targeted interventions, such as selective androgen receptor modulators (SARMs) and testosterone therapy, demonstrate clear efficacy in improving physical tissue parameters, specifically increasing lean body mass and reducing adiposity in postmenopausal women. However, these interventions have failed to show consistent, significant improvements in subjective energy or patient-reported fatigue.

Mechanistic explanations

• Decreased circulating androgens directly reduce ligand availability for the AR in target tissues. This bioavailable fraction is heavily modulated by Sex Hormone-Binding Globulin (SHBG); for example, elevated SHBG binds circulating testosterone with high affinity, actively lowering free testosterone levels.
• Weakened AR signaling in skeletal muscle downregulates the activation of the intracellular phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Because the PI3K/Akt pathway is a central anabolic node regulating muscle protein synthesis, myofiber hypertrophy, and metabolic homeostasis, its downregulation compromises muscle metabolic maintenance, leading to loss of lean body mass and altered body composition.

Bottom line

• Postmenopausal declines in total and free testosterone weaken AR and downstream PI3K/Akt signaling, directly compromising muscle protein synthesis and body composition. However, "androgen reserve" is not a standard clinical diagnostic category, and these physiological changes do not reliably translate to subjective energy deficits.