Effects of Heterologous Growth Hormones on Hypothalamic and Pituitary Function in Transgenic Mice

Abstract

The expression of the mouse metallothionein-I (mMT) promoter/human growth hormone (hGH) fusion gene in transgenic mice leads to female sterility and major alterations in the function of the hypothalamic-adenohypophyseal system. These alterations include increases in median-eminence norepinephrine turnover and plasma LH levels, and a decrease in plasma prolactin levels in intact males, and an increase in median-eminence dopamine turnover combined with the suppression of plasma prolactin levels in ovariectomized females. To further characterize these changes and to determine whether they are due to the lactogenic or somatotropic activity of hGH, we have studied hypothalamic and pituitary function in transgenic mice expressing mMT/hGH, mMT/hGH- B ‘variant’, or mMT/bGH fusion genes. In males, the expression of the hGH· B gene was associated with a reduction in pituitary prolactin release in vitro and an increase in LH response to LHRH stimulation, while the bGH transgene did not affect any of the examined parameters of LH and prolactin release. Median-eminence norepinephrine turnover was increased in each of the three lines of transgenic males, while median-eminence dopamine turnover was reduced only in animals expressing the hGH · B gene. In ovariectomized females, plasma LH was suppressed by hGH variant expression, while median-eminence norepinephrine turnover was suppressed in both hGH · B and bGH animals. The turnover of dopamine was increased in the median eminence of females expressing either of the human genes (hGH or gHG- · B) and reduced in the median eminence of ovariectomized bGH females. We conclude that the hGH· B gene is weakly lactogenic in mice, and that the chronic stimulation of either GH receptors (by bGH) or both GH and prolactin receptors (by hGH or hGH · B) can lead to profound alterations in the metabolism of hypothalamic neurotransmitters and pituitary hormone release.

Evidence of a role for neuropeptide Y and monoamines in mediating the appetite-suppressive effect of GH

“…Although hypothalamic DA was unaffected by GH, the DOPAC/DA ratio was significantly decreased in the hypothalamus. This result is consistent with reduced DA turnover in the hypothalamus in GH transgenic mice (Steger et al 1991). In the medulla, GH affected DA turnover in the opposite direction.…”

Pituitary estrogen receptor α and dopamine subtype 2 receptor gene expression in transgenic mice with overproduction of heterologous growth hormones

“…In this regard, Johnston et al (1993) demonstrated that DA regulates D2R gene expression in normal rat pituitary cells. In hGH transgenic mice, presumably due to its PRL-like action, hGH is binding to PRL receptors of the tuberoinfundibular dopaminergic neurons and stimulates their function, thus suppressing PRL release (Bartke et al 1988;Steger et al 1991). A similar situation occurs in association with hyperprolactinemia when PRL feedback regulates its own release, in part by influencing the function of tuberoinfundibular neurons (Moore 1987) and by increasing the synthesis and release of DA 238 Fig.…”

GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

“…Indeed, the induction of GH resistance by GHR gene knockout is correlated with a significant reduction in fertility (Chandrashekar & Bartke 1998, Bartke 1999. Exogenous GH, conversely, increases circulating LH levels in dairy cattle (Schemm et al 1990) and the in vitro release of LH and FSH from rodent pituitary glands (Steger et al 1991, Tang et al 1993. The administration of bovine GH to GH-deficient Ames mice also increases plasma LH concentrations (Chandrashekar & Bartke 1993).…”