Gonadotropin-Releasing Hormone (GnRH) Analog Suppression Renders Polycystic Ovarian Disease Patients More Susceptible to Ovulation Induction With Pulsatile GnRH*

Abstract

Pulsatile GnRH administration consistently restores normal reproductive hormone levels and ovulation in women with hypogonadotropic hypogonadism, but is less effective in those with polycystic ovarian disease (PCOD). We pharmacologically created a hypogonadotropic condition with a GnRH analog (GnRH-A) in six women with PCOD to investigate the role of deranged gonadotropin secretion in PCOD and to improve the response to pulsatile GnRH ovulation induction. Before GnRH and GnRH-A treatment the women with PCOD had increased LH pulse frequency [one pulse every 55 ± 2 (± se) min; P < 0.05] and LH pulse amplitude (10.9 ± 1.4 U/L; P < 0.05) compared to normal women in the follicular phase of their menstrual cycle. Each PCOD woman completed one cycle of pulsatile GnRH administration for ovulation induction before (pre-A cycles; n = 6) and one or two cycles after (post-A cycles; n = 9) GnRH-A administration [D-Ser(tBu)⁶–Des,Gly10-GnRH; 300 μg, sc, twice daily for 8 weeks]. Pulsatile GnRH (5 μg/bolus) was given at 60-min intervals using a Zyklomat pump. Daily blood samples were drawn during the pulsatile GnRH ovulation induction cycles for the determination of serum LH, FSH, estradiol (E₂), progesterone, and testosterone, and pelvic ultrasonography was done at 1- to 4-day intervals. Mean (±se) serum LH levels were elevated during the pre-A cycle (49.2 ±3.1 IU/L) and decreased to normal levels during the post-A cycles (19.6 ± 1.4 IU/L; P < 0.0001). Mean testosterone concentrations were lower during the post-A cycles [88 ± 2 ng/dL (3.1 ±0.1 nmol/L)] than during the pre-A cycles [122 ± 3 ng/dL (4.2 ±0.1 nmol/L); P < 0.0001]. In the follicular phase of the post-A cycles E₂ levels were significantly lower [81 ± 5 pg/mL (300 ± 20 pmol/L) vs. 133 ± 14 pg/mL (490 ± 50 pmol/L); P < 0.0001], preovulatory ovarian volume was smaller (24.6 ± 2.0 vs. 31.4 ± 2.4 cm³; P < 0.01), and the FSH to LH ratio was higher (0.56 ± 0.03 vs. 0.16 ± 0.01) than in the pre-A cycle, suggesting more appropriate function of the pituitary-gonadal axis. Excessive LH and E₂ responses to pulsatile GnRH administration in the early follicular phase of the pre-A cycle were abolished in the post-A cycles. Mean luteal phase progesterone levels were higher in the post-A [10.6 ± 0.7 ng/mL (34 ± 2 nmol/D] than in the pre-A cycles [8.0 ± 0.7 ng/mL (25 ± 2 nmol/L); P < 0.01]. One pregnancy occurred in six pre-A cycles, while four conceptions were achieved in nine post-A cycles. These data indicate that 1) pulsatile GnRH administration to PCOD patients further impairs deranged gonadotropin and gonadal steroid secretion; 2) a more normal follicular phase and corpus luteum function can be achieved with pulsatile GnRH if PCOD patients are rendered hypogonadotropic by GnRH-A administration; 3) deranged gonadotropin secretion and excessive pituitary sensitivity are key components in the abnormal response of PCOD patients to pulsatile GnRH administration.