Does low free testosterone reduce glucose disposal capacity in women?

The physiological relationship between androgens, muscle mass, and glucose metabolism in women involves a complex interplay between anabolic signaling and metabolic regulation. While androgens and skeletal muscle are critical to glucose homeostasis, the direction of the relationship between testosterone and glucose disposal is markedly different in women compared to men.

Clinical and metabolic evidence

Skeletal muscle is established as the primary site for insulin-stimulated glucose uptake, responsible for approximately 70% to 90% of whole-body glucose disposal under healthy conditions. This process is primarily mediated by the translocation of GLUT4 transporters to the cell membrane via the PI3K-Akt signaling pathway.

However, clinical evidence in women contradicts the notion that low free testosterone impairs glucose disposal:

• Hyperandrogenism and insulin resistance: In women, higher levels of free testosterone—rather than lower levels—are consistently associated with impaired glucose handling and insulin resistance. This is most clearly observed in conditions like Polycystic Ovary Syndrome (PCOS), where androgen excess correlates with elevated HOMA-IR scores and reduced glucose clearance.
• Sex-specific divergence: Unlike in men, where low testosterone is a risk factor for metabolic syndrome, higher free testosterone in women is a marker for increased risk of type 2 diabetes and metabolic dysfunction.
• Interventional findings: Research indicates that when insulin sensitivity is improved (e.g., through metformin), free testosterone levels typically decrease in women, suggesting that hyperinsulinemia may drive androgen elevations rather than low androgens driving insulin resistance.

Mechanistic explanations

Androgens contribute to the maintenance of lean mass through specific molecular pathways, but these effects do not translate into improved glucose disposal in women when testosterone levels are "low":

• Anabolic signaling: Androgens bind to the androgen receptor (AR) in skeletal muscle, activating the Akt-mTOR axis and increasing protein synthesis. While the decline of androgens during menopause can exacerbate sarcopenia (loss of muscle mass), the resulting decrease in "glucose sink" volume does not make low testosterone a primary driver of reduced glucose disposal capacity in female physiology.
• Glucose transport interference: Excess androgens in women may actually impair insulin signaling. High levels of testosterone can interfere with the insulin-signaling cascade in muscle cells, potentially reducing the efficiency of GLUT4 translocation and thereby decreasing glucose uptake despite the presence of muscle mass.

Bottom line

While androgens help maintain the lean mass that serves as the body’s primary site for glucose uptake, the claim that low free testosterone reduces glucose disposal capacity in women is unsupported. In female physiology, it is high free testosterone, not low, that is clinically associated with impaired insulin sensitivity and reduced glucose disposal.