Gonadotropin secretion, synthesis, and gene expression in human growth hormone transgenic mice and in Ames dwarf mice.

The expression of the mouse metallothionein-I (MT) promoter/human GH (hGH) fusion gene leads to reduced fertility and increased plasma LH levels in male MT/hGH transgenic mice. To determine the effects of hGH on gonadotropin synthesis and release, we have examined basal and GnRH stimulated LH and FSH release in pituitary incubations and perifusions; and pituitary content of LH, FSH, LH-beta messenger RNA (mRNA), and FSH-beta mRNA in MT/hGH transgenic males and in their normal littermates. For comparison, similar studies were performed in GH and PRL deficient Ames dwarf mice in which plasma gonadotropin levels are known to be reduced. We have also measured the LH and FSH release from normal pituitaries transplanted under the kidney capsule of MT/hGH transgenic or normal mice. We found that in MT/hGH transgenic mice, there were parallel increases in unstimulated and GnRH stimulated LH release from pituitary incubation, in pituitary LH content and in LH-beta mRNA levels. In pituitary perifusion, the basal LH secretion was elevated, whereas LH responses to GnRH pulses were not altered. In transgenic males, FSH-beta mRNA was increased, whereas basal and GnRH-stimulated FSH release and pituitary FSH content did not differ from their normal controls. After normal pituitaries were transplanted to kidney capsules of MT/hGH transgenic mice, the expected decrease in LH and FSH secretion was attenuated and the responsiveness to GnRH stimulation was maintained. In Ames dwarf mice, all gonadotropin content and release, as well as pituitary beta-mRNA contents were decreased. We conclude that in MT/hGH transgenic mice, the expression of LH-beta and FSH-beta gene is increased. In addition, there is a translational or posttranslational inhibitory influence on FSH synthesis. Although our previous studies suggest that the effects of hGH gene expression on LH and FSH release are exerted primarily at the hypothalamic level, the present results suggest existence of GnRH unrelated peripheral factors which can directly stimulate pituitary gonadotropin synthesis and release. In Ames dwarf mice, the deficiency of GH and PRL, as well as TSH, is associated with decreased LH-beta and FSH-beta gene expression which may account for the reduction in plasma gonadotropin levels.