The midcycle surge of LH and FSH is critical for final oocyte maturation and ovulation. In normal women, this gonadotropin surge follows a gradual increase in estradiol levels (E) and is concomitant with a small increase in progesterone (P) levels. However, whether sex steroids alone are sufficient to induce the complex neuroendocrine interactions underlying this switch from negative to positive feedback is unknown. In this study, physiological midcycle levels of E, with and without periovulatory levels of P (E+P and E, respectively) were infused into 18 normally cycling women in their early to midfollicular phases. The resulting sex-steroid-induced gonadotropin responses were then compared with 118 spontaneous midcycle surges in 81 normal women. The sex steroid levels achieved by the infusions were within the normal ranges for the spontaneous midcycle surge. However, neither women who received E alone nor those who received E+P had LH responses that achieved those of spontaneous LH surges in the normal menstrual cycle (NMC) [82.7 +/- 16.23 IU/L E (mean +/- SEM), 69.7 +/- 12.01 IU/L E+P vs. 121.7 +/- 6.23 IU/L NMC, P < 0.05 E and P < 0.005 E+P vs. NMC]. In contrast, peak FSH levels evoked by E and P matched the spontaneous FSH peaks (19.0 +/- 2.1 IU/L E, 24.5 +/- 4.0 IU/L E+P vs. 23.3 +/- 0.9 IU/L NMC, P = 0.07 E and P = 0.71 E+P vs. NMC). In conclusion, sex steroids alone do not seem to be sufficient to stimulate the normal midcycle LH surge. We hypothesize that other ovarian factors, which are missing in the midfollicular phase, are required for the generation of the normal midcycle surge of LH.