Estradiol Stimulation of Pulsatile Gonadotropin-Releasing Hormone Secretionin Vitro: Correlation with Perinatal Exposure to Sex Steroids and Induction of Sexual Precocityin Vivo

Abstract

Our aim was to study the effect of estradiol (E2) on pulsatile GnRH secretion in vitro in relation to sex and development. When hypothalamic explants obtained from 5- and 15-d-old female rats were exposed to E2 (10(-7) m), a reduction of GnRH interpulse interval (IPI) occurred but not at 25 and 50 d of age. This effect was prevented by the estrogen receptor antagonist ICI 182.780 and the AMPA/kainate receptor antagonist DNQX but not by the AMPA and N-methyl-d-aspartate receptor antagonists SYM 2206 and MK-801. E2 did not affect GnRH IPI in hypothalamic explants obtained from male rats. Therefore, the possible relation between the female-specific effects of E2 in vitro and perinatal sexual differentiation was investigated. When using explants obtained from female rats masculinized through testosterone injection on postnatal d 1, E2 was no longer effective in vitro at 5 and 15 d. In addition, with explants obtained from male rats demasculinized through perinatal aromatase inhibitor treatment, E2 became capable of decreasing GnRH IPI in vitro at 15 d. To study the possible pathophysiological significance of early hypothalamic E2 effects, female rats received a single E2 injection on postnatal d 10. This resulted in reduced GnRH IPI in vitro on d 15 as well as advancement in age at vaginal opening and first estrus. In conclusion, E2 decreases the GnRH IPI in the immature female hypothalamus in vitro through a mechanism that depends on perinatal brain sexual differentiation and that could be involved in some forms of female precocious puberty.

Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: A review of rodent and human data

“…When administered after PND 20, E2 also advanced the age at VO (Edgren et al, 1966;Ashby et al, 1997a,b;Odum et al, 1997). Early VO and first estrus were also observed in our laboratory after a single massive dose of E2 (10 mg/kg day) given on PND 10 (Matagne et al, 2004). Cycling disturbances were found after treatment during the first 10 postnatal days as a possible result of disturbed sex differentiation of central nervous system.…”

“…This effect suggests a central stimulatory involvement, resulting from acceleration in hypothalamic maturation. Such an hypothesis was supported by the increase in GnRH pulse frequency seen after in vivo and in vitro E2 administration (Matagne et al, 2004). Irregular cyclicity followed by persistent estrus or diestrus, associated with subfertility or complete sterility was shown in most studies with all types of EDCs, indicating an additional disturbing impact on the hypothalamic functions.…”

“…The effects of steroids or some EDCs on such endpoints will be discussed below. In our laboratory, the developmental increase in frequency of pulsatile GnRH secretion in vitro has been shown to be particularly sensitive to sex steroids administered in vitro or in vivo around the age of 10-15 days (Matagne et al, 2004). Thus, the immature female rat provides a condition with high sensitivity of the HP unit to the inhibitory and stimulatory effects of estrogens.…”

“…In the rodent, programming of the central mechanism of ovulation takes place between the last week of prenatal life and the first week of postnatal life (Naftolin, 1994). Early exposure to sex steroids causes disturbances in that process (Matagne et al, 2004) whereas, in the human female, there is no convincing evidence of a similar mechanism (Grumbach and Styne, 2003).…”

“…However, E2 was found to stimulate GnRH secretion by these GT1-7 cells, an effect mediated by transforming growth factor (TGF)βl derived from astrocytes (Zwain et al, 2002). Recently, a stimulation of GnRH pulse frequency was observed using hypothalamic expiants of immature female rats either incubated with E2 in vitro or after E2 administration in vivo (Matagne et al, 2004). Scarce data on pituitary function were obtained.…”