Context: There is considerable evidence that metabolic factors such as insulin resistance may induce hyperandrogenemia in PCOS. However, other metabolic factors such as free fatty acids (FFAs) may also contribute to androgen excess.

Objective: To study effects of FFAs on adrenal production of androgen precursors in vivo.

Design and Participants: We investigated 8 healthy young men, as male individuals produce the androgen precursors DHEA, DHEAS and androstenedione predominantly in the adrenal gland. A randomized controlled cross-over trial was performed.

Intervention: Following a 10-hour overnight fast, 20% lipid/heparin or saline/heparin infusion was given at a rate of 1.5 ml/min. 4 h after start of lipid infusion, an euglycemic hyperinsulinemic clamp was performed.

Main Outcome Measures: DHEA, androstenedione, 17-OH-progesterone, testosterone, estrone, LH, FSH, ACTH and cortisol were measured.

Results: The adrenal androgen precursors DHEA and androstenedione showed a circadian decline during saline/heparin infusion (P < 0.05 vs. baseline, respectively), while no significant changes were observed during lipid/heparin infusion (p= n.s. vs. baseline, respectively). Correspondingly, DHEA and androstendione values were significantly elevated during lipid compared with saline infusion (P < 0.05, respectively) and AUCs of both androgen precursors were significantly increased with lipid compared with saline infusion. Notably, all changes were detected before induction of insulin resistance.

Conclusions: This study demonstrates that FFAs increase production of androgen precursors in vivo in men. These data tentatively suggest, that hyperandrogenemia in PCOS may at least in part be induced by elevated free fatty acids.