Gonadotropin-releasing hormone pacemaker sensitivity to negative feedback inhibition by estradiol in women with hypothalamic amenorrhea

To better understand the pathophysiology of hypothalamic amenorrhea (HA), the frequency of luteinizing hormone (LH) pulsatility and the LH response to gonadotropin-releasing hormone (GnRH) was assessed before and after clomiphene citrate (CC) in 18 women with HA and 10 normal women in the early follicular phase (EFP). The HA women showed a greater acceleration of LH pulsatility after CC than EFP women but there was a decrease in their LH response to GnRH. Naloxone caused an increase in LH pulsatility in HA but not EFP women, although this effect was less than that seen with CC. We conclude that, in HA women, the GnRH pacemaker, but not the pituitary, is inhibited by increased sensitivity to the negative feedback effect of estradiol and increased opiate tone.