The gonadotropin-releasing activity of synthetic αMSH, previously found in normal men, was evaluated in women with different hormonal environments and in patients with acyclic gonadotropin release due to hypothalamic-pituitary dysfunction. αMSH (2.5 mg, iv) administered as either a single or two repeated pulses (at 2-h intervals) elicited unequivocal pituitary release of LH in normal women during the luteal phase and midcycle surge and in patients with functional hypothalamic amenorrhea, hyperprolactinemic amenorrhea, and polycystic ovary syndrome. Concomitant release of LH and FSH occurred only in polycystic ovarian syndrome patients and normal men. αMSH had no discernible effect on gonadotropin release in women during the early and late follicular phases of the cycle, in postmenopausal women, and in patients with isolated gonadotropin deficiency, even after pulsatile GnRH priming. The present observations confirm and extend our earlier finding that αMSH possesses gonadotropin-releasing activity in men and indicate that αMSH has similar properties in women with progesterone- and androgen-dominated environments or with specific types of hypothalamic-pituitary dysfunction marked by attenuated GnRH-LH release.