Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women.

Abstract

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.

Ovarian feedback, mechanism of action and possible clinical implications

“…According to this hypothesis, the role of GnSAF in humans is to control the amplitude and not the onset of the LH surge. In fact, an endogenous LH surge occurs invariably as a response to the positive feedback effect of E 2 either in the early-or in midfollicular phases of the normal menstrual cycle, but this surge is attenuated as compared to midcycle (Taylor et al, 1995;Messinis et al, 2001). Therefore, E 2 and GnSAF seem to interact at the pituitary gonadotrophs with the former expressing a sensitizing effect and the latter an antagonistic effect.…”

Progesterone administration does not acutely alter LH pulse secretion in the mid-follicular phase in women

“…Subjects in that study had estradiol levels similar to the levels observed in this study; and it is possible that the threshold estradiol level necessary for progesterone-related augmentation of gonadotropin release may be different depending on the developmental maturation stage. Alternatively, there may be other cycle phase relevant factors that impact positive feedback effect of progesterone on gonadotropin release (Taylor et al 1995).…”

Modulatory Effect of the Ovary on LH Secretion

“…Indeed, an endogenous LH surge is induced invariably during the early or midfollicular phase of the cycle when E2 concentrations exceed the threshold level for the positive-feeback effect, but the surge in these cases is markedly attenuated as compared to the midcycle LH surge. 28,29 In conclusion, it is clear that E2 and progesterone are important regulators of basal LH and FSH secretion in the normal menstrual cycle. Superovulated ovaries produce GnSAF, which attenuates the endogenous LH surge.…”