Gonadotrophin-releasing hormone modulation of gonadotrophins in the ewe: evidence for differential effects on gene expression and hormone secretion

ABSTRACT While the regulation of gonadotrophin secretion by gonadotrophin-releasing hormone (GnRH) has been well documented in both rats and sheep, its role in the synthesis of gonadotrophin subunits remains unclear. We have investigated the effects of the specific inhibition of GnRH by a GnRH agonist on the expression of gonadotrophin subunit genes and the subsequent storage and release of both intact hormones and free α subunit. Treatment with GnRH agonist for 6 weeks abolished pulsatile LH secretion, reduced plasma concentrations of FSH and prevented GnRH-induced release of LH and FSH. This was associated with a reduction of pituitary LH-β mRNA and FSH-β mRNA levels (to 5 and 30% of luteal control values respectively), but not α mRNA which was significantly increased (75% above controls). While there was a small decrease in the pituitary content of FSH (30% of controls), there was a drastic reduction in LH pituitary content (3% of controls). In contrast to the observed rise in α mRNA, there was a decrease in free α subunit in both the pituitary and plasma (to 30 and 80% of control levels). These results suggest that, while GnRH positively regulates the expression of both gonadotrophin β-subunit genes, it can, under certain circumstances, negatively regulate α-subunit gene expression. Despite the complete absence of LH and FSH in response to GnRH, there remained a basal level of β-subunit gene expression and only a modest reduction (50%) in the plasma levels of both FSH and LH, suggesting that there is a basal secretory pathway. The dramatic reduction in LH pituitary content indicates that GnRH is required for the operation of a regulatory/storage pathway for the secretion of LH. There appears to be no similar mechanism for FSH. The LH-specific pathway is probably dependent upon the availability of LH-β subunits which subsequently plays a role in regulating α subunit by sequestering, assembling and storing the intact hormone in the presence of GnRH. Finally, in the absence of responsiveness to GnRH, the regulation of α-subunit production is not at the level of gene transcription. Inefficient translation of the mRNA or rapid degradation of the free α chain may account for the observed dramatic decrease in production of α subunit.