Endocrine dynamics during pulsatile GnRH administration in patients with hypothalamic amenorrhea and polycystic ovarian disease

Abstract

The LH secretory patterns and ovarian endocrine responses have been determined during pulsatile gonadotropin-releasing hormone (GnRH) administration for induction of ovulation in patients with hypothalamic amenorrhea (HA). However, until now these endocrine dynamics during GnRH therapy have not been thoroughly investigated in patients with polycystic ovarian disease (PCOD). Seven patients with HA and 4 patients with PCOD have therefore been studied to determine changes in LH pulsatile activity and in serum sex steroid levels in response to chronic intermittent GnRH stimulation. GnRH was administered intravenously (5-10 μg/90 minutes) by means of a portable infusion pump. Blood samples were obtained at 15-minute intervals for 4 hours on the day before the start of GnRH stimulation (control day) and on treatment days 5, 10 and 15. LH was determined in all samples and FSH, serum androgens and estrogens were measured in baseline samples by RIA.

While 8 (62%) ovulations and 5 conceptions were observed in 13 treatment cycles in patients with HA, no ovulations were achieved during 9 treatment cycles in patients with PCOD. On the control day significantly (p < 0.05) higher basal LH and testosterone (T) levels and significantly (p < 0.05) lower FSH levels were found in the PCOD patients. The LH pulsatile profiles of the PCOD patients showed significantly (p < 0.05) higher pulse amplitudes and areas under the curve (integrated responses). Pulsatile GnRH administration induced a significant (p < 0.05) increase in LH pulse amplitudes in both HA and PCOD patients, and also increased (p < 0.05) the integrated responses in patients with HA. During the GnRH stimulation, the LH interpulse intervals of both HA and PCOD patients were found to be similar to the frequency in which exogenous GnRH was administered. FSH levels rose continuously (p < 0.001) during stimulation in patients with HA, but remained unchanged in patients with PCOD. In HA patients, T, androstenedione (AD) and estrone (E₁) did not change during the GnRH treatment, but estradiol (E₂) rose so that the ratios of aromatized estrogens to non-aromatized androgens (E₁/AD, E₂/T) increased. In contrast, T and AD increased significantly (p < 0.05 or less) and E₂ remained unchanged during stimulations in PCOD patients, which resulted in decreasing ratios of estrogens to androgens.

These observations confirm that pulsatile GnRH administration can successfully induce ovulation in patients with HA by restoring the ovarian physiology. The data also demonstrate that pulsatile GnRH administration can influence the LH secretory patterns in PCOD patients. However, presumably due to insufficient FSH stimulation, the ovarian androgenization persists in PCOD patients and results in a failure of GnRH treatment to induce ovulation.