Is steroid deficiency the cause of tolerance in nitrate therapy?

The award of the Nobel Prize in Physiology and Medicine for 1998 bears witness to the ‘explosive’ field of nitric oxide (NO), and who would have thought the explosive nitroglycerin owed its therapeutic effectiveness to this little molecule? NO is also involved in causing penile erection, which has brought sildenafil to the aid of patients with erectile dysfunction. However, emerging evidence in animals and in vitro studies indicates that NO also inhibits steroidogenesis, which may have repercussions in humans. The decrease in androgen secretion may impact on secondary sexual characteristics, including penile size. The tolerance to the nitrate therapy in angina, characterized by volume expansion and not due to sodium retention, may also be related to steroid hormone deficiency. Decreased cortisol secretion may impair water excretion, resulting in volume expansion. Impaired aldosterone secretion would cause hyponatraemia with resultant raised renin. I hypothesize that continuous therapy with nitrates and sildenafil will result in diminished levels of steroid hormones with predicted sequelae.