Can low androgen availability reduce tissue-level androgen signaling in women even when estradiol is normal?

Androgen receptor (AR) signaling in women contributes to musculoskeletal and bone physiology and sexual function, so low androgen availability can reduce tissue-level androgen signaling even when estradiol is normal.

Musculoskeletal and bone health

• Bone preservation: AR signaling is a major regulator of bone homeostasis in females. In preclinical models, the selective knockout of ARs in osteoblasts and osteocytes of female mice leads to a significant reduction in trabecular bone volume fraction (BV/TV by ~20-30%) and compromised cortical bone quality.
• Muscle mass and function: Bioavailable testosterone levels and nuclear AR localization correlate positively with skeletal muscle mass and handgrip strength in women. Myogenic cells in females display high sensitivity to low androgen concentrations, translocating AR to the nucleus to maintain myofibrillar organization and muscle protein synthesis.

Sexual function and motivation

• Central and peripheral activation: AR activation directly modulates female sexual behavior and desire. In animal models, the administration of selective androgen receptor modulators (SARMs) or non-aromatizable androgens (such as DHT) significantly increases sexual motivation, independently of estrogen receptors.
• Clinical response: Postmenopausal women with Hypoactive Sexual Desire Disorder (HSDD) treated with transdermal testosterone show significant improvements in satisfying sexual events (treatment effect size of ~0.3-0.4 over placebo, p < 0.05) and sexual desire, confirming that direct androgenic pathways play an essential role in female sexual health.

Independence from estradiol levels

• Autonomy of the androgen receptor: AR and estrogen receptors (ER) regulate distinct genomic targets. Estrogen cannot substitute for AR-mediated transcription.
• Intracrine synthesis: Female tissues (bone, brain, and muscle) rely heavily on intracrine enzymes to convert circulating precursors like DHEA into active androgens locally. When these precursors or local androgens are deficient, tissue-level AR signaling is compromised, resulting in suboptimal bone and sexual function even when serum estradiol remains fully normal.

Bottom line

Low androgen availability impairs essential musculoskeletal, bone, and sexual functions in women through reduced tissue-level AR signaling, a deficit that normal circulating estradiol levels cannot compensate for.