Pulsatile Gonadotropin Secretion in Women with Hypothalamic Amenorrhea: Evidence that Reduced Frequency of Gonadotropin-Releasing Hormone Secretion Is the Mechanism of Persistent Anovulation*

Abstract

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.

Neuroendocrine Abnormalities in Hypothalamic Amenorrhea: Spectrum, Stability, and Response to Neurotransmitter Modulation1

“…Seventy-five percent of patients studied repeatedly met criteria for at least two different classifications, and 33% reverted at least once to an unclassified pattern. The variability of LH secretion abnormalities observed in this large sample of patients studied over time confirms earlier data reported in smaller series that showed similar variability (5,29). This may imply that most HA patients do not have a static defect in GnRH secretion, but rather have changing patterns of GnRH secretion that vary over time and are insufficient to support ovulation or folliculogenesis.…”

“…HA accounts for up to 48% of secondary amenorrhea (1) and is of particular clinical importance as the hypoestrogenism associated with HA has been correlated with decreased bone density (2,3). Previous work, including our own, suggests that this disorder represents a spectrum of abnormal patterns of endogenous hypothalamic GnRH release (4,5). HA has been associated with increased exercise, decreased weight, and stress in some patients, while in many, no inciting features can be identified.…”

“…In contrast, previous neuroendocrine studies in patients with HA have demonstrated evidence of pulsatile LH secretion in most HA patients. Some report a lower mean frequency of LH pulses in HA patients than in normally cycling women (6,7), while other studies have demonstrated a broader neuroendocrine spectrum, from complete absence of LH pulsations to normal-appearing secretion patterns (4,5).…”

“…Previous studies exploring the stability of secretion patterns over time used small numbers of subjects or suboptimal blood-sampling intervals (4,5,7). The variability in underlying patterns of GnRH secretion and the variable response to neurotransmitter modulation raises the question of whether response to specific neuromodulation may correlate with a specific pattern of GnRH secretion, for example slow frequency or lack of LH secretion with unresponsiveness to naloxone (17).…”

Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors

“…Disruption of the correct pulsatile GnRH pattern and, hence, gonadotropin synthesis and secretion, manifests itself in a number of clinical disorders that cause infertility. In women, hypothalamic amenorrhea is predominantly associated with low GnRH pulse frequencies and abnormal serum gonadotropin levels (40); conversely, PCOS is associated with both high GnRH pulse frequencies and circulating LH levels but reduced circulating FSH levels (3,12,13).…”