Context: Low-dose testosterone replacement therapy in women with relative androgen deficiency has been shown to have beneficial effects on body composition, bone mass and psychosexual function. However, the safety of chronic testosterone administration on cardiovascular risk and insulin resistance is unknown.

Objective: To determine the effects of physiologic testosterone replacement on cardiovascular risk markers and insulin resistance in women.

Design: 12-month randomized, placebo-controlled study

Setting: General Clinical Research Center

Study Participants: 51 women of reproductive age with androgen deficiency due to hypopituitarism

Intervention: Study participants were randomized to physiologic testosterone administration, 300 mcg daily, or placebo, by patch.

Main Outcome Measures: Fasting glucose, fasting insulin, IRHOMA, QUICKI, hsCRP, VCAM, leptin, Lp(a), apoA1, and homocysteine.

Results: At 12 months, fasting insulin and HOMA were significantly lower in the testosterone compared with the placebo group, and there was a trend toward a higher QUICKI level at 12 months in the testosterone compared with the placebo group. These differences were no longer significant after controlling for baseline levels. We observed no effect, either positive or negative, of testosterone administration on hsCRP, VCAM, leptin, Lp(a), or apoA1.

Conclusions: Our data suggest that physiologic testosterone replacement in women with hypopituitarism for 12 months does not increase, and may improve, insulin resistance. Chronic low-dose testosterone administration does not increase markers of cardiovascular disease reflecting several different mechanistic pathways. Large, randomized, placebo-controlled, long-term prospective studies are needed to determine whether low-dose testosterone replacement affects cardiovascular risk and event rates in women.