Assessment of Estradiol-Induced Gonadotropin Surge Generation: Preliminary Results From a Protocol of Graded Transdermal Estradiol Dosing

In normally-cycling women, high midcycle estradiol (E2) concentrations (> 200-300 pg/ml) derived from the dominant follicle trigger an approximately 10-fold increase in LH and 4-fold increase in FSH levels—the gonadotropin surge—over about 48 hours. In prenatally-androgenized female rats and sheep (animal models with polycystic ovary syndrome [PCOS]-like features), high-dose estrogen fails to initiate gonadotropin surges. However, it remains unclear whether E2-induced gonadotropin surge generation is defective in PCOS. Baird et al., induced LH surges in 12 women with PCOS and 6 normally-cycling controls (studied in the early follicular phase) with 3 days of high-dose oral ethinyl E2, and the LH peak magnitude was similar in both groups (JCEM 1977;45:798-801). However, the dose of ethinyl E2 in this study (200 mcg/day) was markedly supraphysiological, and the dosing schedule did not mimic the normal, gradual increase in E2 levels observed in normal follicular phases. To further assess potential impairments in E2 augmentation of gonadotropin secretion in PCOS, we developed a study protocol involving graded transdermal E2 dosing (with dose adjustments as needed) to gradually achieve serum E2 concentrations approximating 300-400 pg/ml. Herein we present our early experience with this protocol in six normally-cycling, non-hyperandrogenic women: median (range) age 23.1 (19.8–29.0) years, body mass index 20.7 (19.2–27.2) kg/m2, calculated serum free testosterone 2.7 (2.4–5.3) pg/ml. Study subjects began transdermal E2 on cycle day 4 with the following dose-escalation protocol: 0.2 mg/d x 1 day, then 0.3 mg/d x 1 day, then 0.4 mg/d x 1 day, then 0.5 mg/d. Daily serum E2 measurements informed dose adjustments (e.g., a measured E2 level > 400 pg/ml prompted a dose reduction; a measured E2 level < 250 pg/ml while on the 0.5 mg/d dose prompted a dose increase to 0.6 mg/d). In these six women, daily E2 values (pg/ml) were as follows: baseline 31 (17–36) (median [IQR]) on cycle day 4 (the morning of E2 initiation); 205 (135–240) on day 5; 159 (135–270) on day 6; 263 (202–363) on day 7; 276 (239–351) on day 8; 328 (307–367) on day 9; 333 (269–402) on day 10; and 328 (253–354) on day 11. Median transdermal E2 doses (mg/d) on days 5 through 11 were 0.2, 0.3, 0.4, 0.35, 0.4, 0.4, and 0.4, respectively. Morning serum LH concentrations (median [IQR]) were 5.2 (3.5–6.1) IU/L immediately before E2 initiation (cycle day 4), decreased to a nadir of 1.5 (1.0–2.4) IU/L after 2 days of E2 (cycle day 6), thereafter increasing 8.1-fold to a peak of 12.1 (8.1–18.3) IU/L after 5 days of E2 (cycle day 9). FSH similarly changed from baseline median 3.5 (3.4–4.2) IU/L to nadir median of 1.6 (1.2–1.8) IU/L after 2 days of E2, thereafter increasing again to 3.5 (2.6–4.0) IU/L after 5 days of E2. We conclude that this experimental protocol may be useful to investigate potential defects in E2-induced LH surge generation in PCOS.