Hypothalamic amenorrhea (HA) is a clinical disorder of unknown etiology. The diagnosis is made by exclusion of known abnormalities of pituitary and ovarian function. To determine if abnormalities of GnRH secretion could account for the anovulation and amenorrhea, we measured plasma gonadotropins every 20 min for 10- to 24-h periods in 19 women with HA. Ovarian steroids and gonadotropin responses to an iv bolus dose of GnRH (25 ng/kg) were also measured. The results were compared to those obtained during the early follicular (EF) and late luteal (LL) phases of ovulatory cycles in normal women. Plasma estradiol was lower (mean +/- SE, 52 +/- 5 pg/ml) than either cycle stage in normal women. Mean plasma LH was lower than EF values and FSH was higher than LL values. The amplitude of LH pulses in HA was similar to that in normal women. LH pulse frequency was the same as that present during the LL, but lower than that during the EF (HA, 4.7 pulses/12 h; EF, 7.7 pulses/12 h; P less than 0.05). In addition to the similar frequency, the patterns of LH secretion in HA resembled that of LL in that the amplitude of LH pulses was highly variable and pulses occurred at irregular intervals. Consistent changes in diurnal gonadotropin secretion were not found, and LH secretion was greater at night in 9 studies and during the day in 5 studies. Repeat studies in three patients (5-13 months later) revealed that LH pulse frequency was variable, being unchanged in 1, increased in 1, and decreased in the third patient. Thus, LH pulse frequency and, by inference, GnRH pulse frequency are similar in HA to those in the normal luteal phase despite a different steroid milieu. GnRH pulse frequency increases from the luteal to the follicular phases of normal cycles and may be important in the initiation of ovarian follicular maturation. These data suggest that the absence of cyclical gonadotropin secretion and anovulation in HA result from a decreased frequency and irregular amplitude of GnRH secretion and consequent absence of ovarian follicular maturation.

Pulsatile gonadotropin secretion was examined in seven women with hyperprolactinemia and amenorrhea by obtaining blood samples every 20 min for 24 h. When plasma PRL had returned to normal and menses had resumed during bromocriptine treatment, five women were restudied in an identical manner during the early to midfollicular stage of their cycles. Gonadotropin responses to a small dose of synthetic GnRH (25 ng/kg, iv) were measured after the initial 24-h study in each patient. In addition, low dose pulses of GnRH (25 ng/kg) were administered iv every 2 h for 88 h to three hyperprolactinemic women, and LH and FSH responses were determined. Before treatment with bromocriptine, mean +/- SE plasma gonadotropin concentrations (LH, 5.8 +/- 0.2 mIU/ml; FSH, 4.4 +/- 0.1 mIU/ml) were comparable to values during the follicular phase of normal menstrual cycles. LH pulse frequency during the pretreatment study in the hyperprolactinemic women (mean +/- SE, 7.6 +/- 1.2 pulses/24 h) was significantly less than that found during the early follicular stage of normal cycles (days 3-5; mean, 15.4 +/- 1.1 pulses/24 h). Mean +/- SE LH pulse amplitude before bromocriptine was 5.2 +/- 0.6 mIU/ml. The pattern of pulsatile LH secretion was highly variable before treatment and was characterized by prolonged periods (6-11 h) of low plasma LH concentrations. LH responses to GnRH were normal or increased (mean maximum increment in LH, 38.5 +/- 15.9; range, 4.3-125.2 mIU/ml), and no evidence of intermittent pituitary refractoriness was found during prolonged (88-h) administration of GnRH pulses. Treatment with bromocriptine was associated with the resumption of menses, and no significant change in mean gonadotropin concentrations. LH pulse frequency was increased (mean +/- SE = 10.2 +/- 1.0 pulses/24 h) and LH pulse amplitude was decreased (mean, 3.9 +/- 0.2 mIU/ml) in four of five patients receiving bromocriptine. Moreover, the pattern of pulsatile LH secretion was more uniform during treatment. We conclude that pituitary responsiveness to GnRH is not impaired in women with hyperprolactinemia and amenorrhea, and that periods of low LH secretion in these women are due to intermittent reductions in GnRH secretion. These observations suggest that the abnormal patterns of pulsatile gonadotropin secretion, and by inference GnRH secretion, are important factors in the etiology of amenorrhea associated with hyperprolactinemia.

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To investigate the effects of alterations in GnRH pulse frequency on gonadotrophin secretion, we administered low dose GnRH pulses (25 ng/kg) at hourly or 2-hourly frequencies to eight normal men. All subjects received GnRH pulses i.v. every 2 h for 88 h. Following this, exogenous GnRH was discontinued in four normal men (Group A, GnRH withdrawal), and the frequency of GnRH injections was increased to one pulse every hour for 24 h in the other four normal men (Group B, hourly GnRH). Blood samples were obtained every 20 min for LH and FSH and every 12 h for testosterone (T) and oestradiol (E2). Plasma LH increased in all subjects during injection of GnRH pulses every 2h. Withdrawal of GnRH pulses in Group A men was accompanied by a fall in mean LH, reductions in LH pulse amplitude (Zf SEM: control 6*5+ 1.0; GnRH withdrawal 4.0 f 0.5 mIU/ml) and pulse frequency (control 5.5 f 0.2; GnRH withdrawal 3.5f0.7 pulsesj12 h), and an increase in plasma E2 (control 122 f 15; GnRH withdrawal 340 f 37 pmol/l). Gonadotrophin responses to GnRH (25 ng/kg) were normal when tested 32 h after GnRH withdrawal. Injection of hourly GnRH pulses in Group B men was accomqanied by a timedependent change in mean LH, which transiently rose, then fell, and subsequently rose to a plateau during the second 12 h period of hourly GnRH. The final rise in LH was accompanied by an increase in LH frequency to 1 1.8 f 0-3 pulses/l2 h. These data suggest that: (1) increases in gonadal steroids decrease LH secretion by reducing the amplitude and frequency of endogenous GnRH pulses; and (2) the normal adult male pituitary requires approximately 12 h to initiate a sustained increase jn LH secretion in response to a doubling in GnRH pulse frequency.