Diurnal Patterns of Pulsatile Luteinizing Hormone Secretion in Hypothalamic Amenorrhea: Reproducibility and Responses to Opiate Blockade and anα2-Adrenergic Agonist*

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Abstract
The pattern of pulsatile GnRH secretion is abnormal in some women with hypothalamic amenorrhea (HA) consequent to previous exercise or weight loss. Both diminished frequency pulsatile LH secretion, and by inference GnRH secretion, and normal LH pulsatility have been reported. We assessed whether the patterns of GnRH secretion varied with time by measuring plasma LH every 15 or 20 min for 24 h on 1–3 occasions during a 10-month period in 14 women with HA (a total of 24 studies). During the day, mean LH pulse frequency [1.0 ± 0.1 (±se) pulses/8 h] was lower than that in normal women in the early follicular phase of their cycles (5.1 ± 0.6), and the frequency in individual HA patients was lower than early follicular phase values in 16 of 17 studies. The slow daytime LH pulse frequency also was a consistent finding, in that the values in repeat studies varied by less than 2 pulses/8 h in all but 1 patient. LH pulse frequency (2.0 ± 0.4 pulses/8 h) was higher and more variable during sleep, and normal early follicular phase frequencies were found in 20% of patients with HA. The mechanisms whereby GnRH pulse frequency is reduced are not known. α-Adrenergic agonist drugs stimulate GnRH pulsatile secretion in rodents, but administration of the α2-agonist clonidine (0.15 mg, orally, at 0800 and 2000 h) did not increase the frequency of LH pulses in 7 women (1.7 ± 0.4 pulses/8 h). In contrast, administration of naloxone (1 mg/m2·h, iv) for 8 h during the day to 14 patients, increased LH pulse frequency (3.3 ± 0.5 pulses/8 h). In 8 of these 14 women, LH pulse frequency (4.9 ± 0.4 pulses/8 h) increased into the range found during the normal early follicular phase, while in the other 6 women pulse frequency was not significantly increased (1.4 ± 0.4 pulses/8 h). Plasma estradiol levels were similar in naloxone-responsive and unresponsive women, but spontaneous LH pulse frequency was higher at night in naloxone-responsive patients (2.9 ± 0.6 vs. 1.4 ± 0.3 pulses/8 h). The presence of nocturnal LH pulses did not predict responsiveness to naloxone, however, and LH pulse frequency was less than 2 pulses/8 h in 4 of the women who responded to naloxone. These data indicate that slow frequency GnRH secretion is a common finding during the day in women with HA. GnRH secretion is more variable at night, suggesting that the mechanisms involved in reducing pulsatile GnRH secretion are less effective during sleep. The results of opiate receptor blockade suggest that excess hypothalamic opiate activity may be the mechanism of reduced GnRH secretion in a majority of patients, but the factors involved in other patients are unknown.

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