Intravenous Administration of Pulsatile Gonadotropin Releasing Hormone in Hypothalamic Amenorrhea: Effects of Dosage*

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Abstract
Eighteen women with well characterized hypothalamic amenorrhea underwent 30cycles of pulsatile GnRH treatment in an effort to examine the role of GnRH dosage in pituitary and ovarian responses. GnRH was administered iv at 2 doses (25 and 100 ng/kg bolus) at a physiological range of frequencies (90 and 60 min) in the follicular phase of the induced cycles. After demonstration of ovulation by ultrasound and clinical parameters, the frequency of GnRH administrationwas progressively slowed from every 60 min to every 90 min and then to every 240 min to mimic theslowing of endogenous LH secretion that occurs during the luteal phase in normal women. The results of these induced cycles were compared to those of 62 ovulatory cycles from normal women. Overall clinical and biochemical results revealed the following. Patients receiving doses of 25ng/kg GnRH successfully ovulated only 80% of the time, with recruitment of a single dominant follicle. Two of 5 patients became pregnant. Peak estradiol levels were significantly lower than normal [261 ± 33 (±SE) vs. 342 ± 11 pg/ml, respectively; P < 0.02]. Integrated luteal phase progesterone production was also significantly reduced in the 25 ng/kg group compared to normal (78±17 vs. 145 ± 8 ng/ml/entire luteal phase, respectively; P < 0.02). All women receiving bolus doses of 100 ng/kg GnRH ovulated; maturation of multiple follicles occurred in 5 of 20 cycles, and6 of 7 women conceived. Peak estradiol values were significantly higher than those in eithernormal women or the 25 ng/kg group (478 ± 48 pg/ml; P < 0.02 for both), with integrated luteal phase progesterone levels significantly higher than those in patients receiving the 25 ng/kg dose (196 ± 25 ng/ml/luteal phase; P < 0.02). This study demonstrates that 1) ovulation and fertility can be achieved with a physiological frequency regimen of pulsatile GnRH administration using bolus doses of both 25 and 100 ng/ kg in women with hypothalamic amenorrhea; 2) the 25 ng/kg dose of GnRH may represent a threshold of stimulation of the pituitary-ovarian axis and recreates cycles with an inadequate luteal phase; and 3) a 100 ng/kg dose of GnRH may well cause a supraphysiological stimulation of the pituitary-gonadal axis.

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