EFFECT OF ESTETROL ON THE NEGATIVE FEEDBACK OF ESTROGENS ON LH SECRETION

Estradiol (E2) is a key regulator of reproduction through its role on the feedback control of gonadotropin secretion by the hypothalamus. E2 effects are mainly mediated via estrogen receptor alpha (ERα) activation by a combination of the nuclear and the membrane-associated pathways. However, the contribution of these mechanisms to the regulation of reproduction is not completely clear. To elucidate this contribution, we used estetrol (E4), a human natural estrogen produced in human at late pregnancy which preferentially binds ERα and in peripheral tissuesacts as an agonist on the nuclear fraction of the receptor but as an antagonist on the membrane fraction.
In ovariectomized adult mice, we assessed the effects of E4 alone (E4: 0.3-3.0mg/kg twice daily) or in combination with E2 (E2:5µg/kg twice daily) on the negative feedback regulation of the secretion of the luteinizing hormone (LH) and the expression of two E2-regulated proteins: kisspeptin (KP) and progesterone receptor (PR).
When used alone, the highest dose of E4 regulated LH secretion to a level similar as E2 and increased the number of PR-expressing neurons in the ventromedial hypothalamic nucleus (VMH) and in the preoptic area (POA), but had not significant effect on the number of KP neurons in the anteroventral periventricular nucleus (AVPV). By contrast, when administered along with E2, E4 had no effect on the negative feedback induced by E2.
In conclusion, the results show that E4 exerts a dose-dependent action similar to that of E2 on the secretion of LH and that high doses of E4 increases the expression of PR in the preoptic area and the ventromedial hypothalamic nucleus. Together these suggest that the negative feedback of estrogens on LH secretion depends on nuclear-depend but no membrane-dependent signaling and of estrogens.