Influence of Hypothalamus and Ovary on Pituitary Function in Transgenic Mice Expressing the Bovine Growth Hormone Gene and in Growth Hormone-Deficient Ames Dwarf Mice1

Abstract

Female transgenic mice expressing the bovine (b) growth hormone (GH) gene exhibit reduced fertility, and GH-deficient dwarf mice are sterile. However, in these animals, the influence of the hypothalamus and ovary on pituitary functions is poorly understood. To address this issue, female Ames dwarf mice received twice-daily injections of either vehicle or bGH (25 micrograms/injection per mouse) for 12 days. Vehicle-injected normal female siblings served as controls. On Day 7, these mice and adult female transgenic mice expressing the bGH gene with mouse metallothionein-I promoter, as well as their normal littermates, were ovariectomized. Two experiments were conducted with each group of mice: on Day 8 after ovariectomy of transgenic mice and their normal siblings, and on Day 4 after ovariectomy of dwarf mice and their normal siblings. In experiment I, mice were primed with 0.5 micrograms estradiol benzoate (EB) in oil and 24 h later received injections of 5 micrograms EB/100 g BW. The next day, these mice received injections of either saline or GnRH (1 ng/g BW), and 15 min later blood was obtained via heart puncture under anesthesia. In experiment II, ovariectomized mice either received injections of oil or were primed with 0.5 micrograms EB and 24 h later treated with 10 micrograms EB/100 g BW in oil. On the next day, blood was obtained as in experiment I. In transgenic mice and in their normal littermates, plasma bGH, FSH, LH, and prolactin levels were measured. In dwarf mice and in their normal siblings, plasma LH and insulin-like growth factor (IGF)-I levels were determined. Bovine GH was secreted in transgenic mice, but this hormone was not detectable in normal siblings. Expression of the GH gene resulted in attenuated (p < 0.001) FSH response to GnRH treatment, while LH response was similar to that in controls. The ovariectomy-induced increases in plasma FSH (p < 0.001) and LH (p < 0.05) levels were decreased in transgenic mice. The absolute circulating FSH levels were also decreased (p < 0.001) in estrogen-treated transgenic mice, while plasma LH level were similar in normal mice and in mice bearing the bGH gene. The ovariectomized transgenic mice were hyperprolactinemic. In ovariectomized dwarf mice, IGF-I was not detectable, and GH treatment induced its secretion. In these mice, plasma LH concentrations were reduced (p < 0.05), and GH treatment increased (p < 0.01) LH secretion. In oil-injected ovariectomized dwarf mice, the plasma LH response to GnRH treatment was reduced (p < 0.001), and GH administration normalized this response. The negative feedback effect of estrogen on LH secretion was decreased (p < 0.025) in dwarf mice. These indicate that the alterations in gonadotropin secretion are dependent on the duration of exposure of neuroendocrine system to bGH and that bGH alters the effects of GnRH and estrogen on gonadotropin secretion in these two widely divergent experimental mouse models.