Do higher circulating androgens in women cause reduced insulin sensitivity and impaired glucose tolerance?

The relationship between hyperandrogenism and metabolic dysfunction in women is well-established, with elevated circulating androgens acting as a significant independent driver of insulin resistance and impaired glucose tolerance (IGT).

Clinical and effectiveness evidence

Large-scale epidemiological studies, including the KORA study and various prospective cohorts, demonstrate that women with high levels of total and free testosterone face a substantially higher risk of metabolic disease.

• Diabetes Risk: Women in the highest quartiles of circulating testosterone have approximately double the risk of developing type 2 diabetes compared to those in the lowest quartiles.
• Insulin Sensitivity: Hyperandrogenism is consistently associated with higher HOMA-IR scores, indicating reduced insulin sensitivity. This association remains significant even after adjusting for body mass index (BMI) and adiposity, suggesting that androgens exert metabolic effects independent of obesity.
• Sex-Specific Divergence: Research highlights a "sexual dimorphism" in androgen action; while higher testosterone is often protective against diabetes in men, it is a potent risk factor for glucose intolerance in women.

Mechanistic explanations

Elevated androgens, specifically dihydrotestosterone (DHT), disrupt insulin action through the androgen receptor (AR) across three primary metabolic tissues:

• Skeletal Muscle: High androgens reduce the expression of the insulin receptor β (IRβ) and increase the inhibitory phosphorylation of IRS-1 at the Ser636/639 sites. This blockade prevents the translocation of GLUT4 to the cell membrane, significantly reducing insulin-mediated glucose uptake.
• Liver: Androgens impair the critical PI3K/Akt/mTORC2 signaling pathway. Specifically, excess androgens reduce Akt phosphorylation at the Ser473 site, which is essential for the liver's ability to suppress glucose production and manage lipid metabolism. Liver-specific deletion of the androgen receptor has been shown to prevent these signaling defects in models.
• Adipose Tissue: Hyperandrogenism interferes with adipokine regulation and reduces levels of SREBP1, a key regulator of lipogenesis. These changes contribute to dysfunctional fat mass expansion and systemic inflammation, which further exacerbate insulin resistance.

Clinical implications

The interaction between androgens and insulin is often bidirectional. While excess androgens impair insulin signaling, the resulting compensatory hyperinsulinemia can further stimulate the ovaries to produce more androgens. This creates a self-reinforcing cycle that accelerates the progression toward impaired glucose tolerance and type 2 diabetes. For women with hyperandrogenic conditions, such as PCOS, monitoring and managing androgen levels is critical not just for reproductive health, but as a core component of metabolic risk reduction.

Bottom line

Higher circulating androgens in women directly impair insulin signaling in muscle, liver, and adipose tissue, leading to a significantly increased risk of impaired glucose tolerance and a doubling of the risk for type 2 diabetes.