Role of GnRH in the regulation of pituitary GnRH receptors in female mice.

Abstract

The fall in pituitary GnRH receptors in female mice after ovariectomy (Ovx) was further decreased (greater than 50%), rather than prevented, by treatment with a GnRH antiserum, despite suppression of the post-gonadectomy increase in serum gonadotrophins, suggesting that increased endogenous GnRH secretion is not the mediator of GnRH receptor fall after ovariectomy in mice. Furthermore, GnRH antiserum reduced GnRH receptors by 30-50% in intact normal females, without altering receptor affinity, and rendered serum LH and FSH undetectable but did not reduce receptors in GnRH-deficient, hpg mice. When GnRH was administered to ovariectomized mice this failed to restore receptor values (fmol/pituitary) (intact = 55.3 +/- 2.4; Ovx = 30.1 +/- 2; Ovx + GnRH = 31.6 +/- 2.8), but serum LH was reduced from high post-ovariectomy values (231 +/- 42 ng/ml) to values normal for intact females (24 +/- 2 ng/ml). In contrast, multiple GnRH injections to intact female mice increased GnRH receptor by 35%, while serum LH was reduced to just detectable levels. A marked dissociation between GnRH receptor and serum gonadotrophin concentrations was observed. Administration of oestrogen (E2) plus progesterone (P) to ovariectomized mice in which endogenous GnRH had been immunoneutralized reversed the inhibitory effect of GnRH antiserum on GnRH receptors and increased values above those of ovariectomized controls, although no increase in serum or pituitary gonadotrophin levels was seen in ovariectomized mice treated with E2 + P + GnRH antiserum. Treatment with E2 and P of intact females receiving GnRH antiserum did not prevent the inhibitory effect of antiserum on receptors, while E2 + P treatment alone of intact female mice reduced GnRH receptors by 30%. These data suggest that the gonadal steroids reduce GnRH receptors in intact female mice by inhibiting hypothalamic GnRH secretion, and that a certain degree of pituitary exposure to GnRH is required for maintenance of a normal receptor complement. These results suggest that (1) the fall in GnRH receptors after ovariectomy is primarily attributable to removal of gonadal factors. The fall is not a reflection of alteration in endogenous GnRH interaction with the gonadotroph; (2) homologous ligand 'up-regulation' of GnRH receptors in female mice depends upon the presence of the ovaries; (3) endogenous GnRH is also required for GnRH receptor maintenance in intact female mice; and (4) GnRH receptor and serum gonadotrophin responses to hormonal changes can be dissociated and their relationship is complex.