An Immunocytochemical and Ultrastructural Study of Adenohypophyses of Mice Transgenic for Human Growth Hormone*

Abstract

Adenohypophysial morphology in 12 mice transgenic for methallothionein-I-human (h) GH fusion gene was investigated by immunocytochemistry and electron microscopy. The sustained oversecretion of hGH stimulated body growth. The pituitary glands of 6-month-old transgenic mice were significantly decreased in weight and showed marked morphological changes in somatotrophs, lactotrophs, corticotrophs, and gonadotrophs. GH-immunoreactive cells were greatly reduced in size and midly decreased in number; by electron microscopy, the organelles implicated in hormone synthesis were inconspicuous in this cell type. Transgenic males were hypoprolactinemic, presumably due to lactogenic activity of hGH in rodents. Their pituitaries displayed few and slender PRL-immunoreactive cells; ultrastructurally, they belonged to immature (type II) lactotrophs. However, in females, PRL-containing cells showed no change in number, size, or distribution compared to controls. Prior biochemical studies demonstrated high blood levels of LH in males. Their pituitaries contained highly active gonadotrophs resembling gonadectomy cells, consistent with the view that these changes are related to PRL-like activity of hGH in mice. In both sexes, stimulated corticotrophs were present. The results indicate that some changes in adenohypophysial cells of mice transgenic for hGH can be attributed to protracted overproduction of the heterologous GH, whereas others can be explained by lactotrophic activity of hGH in mice. The divergent morphological responses of lactotrophs and gonadotrophs in the two sexes may reflect differences in the hormonal regulatory mechanisms between male and female mice.

Can Growth Hormone (GH) Accelerate Aging? Evidence from GH-Transgenic Mice

“…In both MT-GH- and PEPCK-GH-Tg mice, the production of transgene-derived GH continues throughout the life span of the animals and is not subject to the physiological mechanisms that normally control GH release. Chronically elevated levels of GH in the peripheral circulation and the consequent increase in the production of IGF-1 lead to suppression of biosynthesis and release of endogenous GH by the pituitary [37, 38, 39]. In most of the currently available lines of GH-Tg mice, the males are fertile, although their breeding performance may be quantitatively reduced and their reproductive life span is usually shortened [reviews in 40, 41].…”

Elevated Corticosterone Levels in Transgenic Mice Expressing Human or Bovine Growth Hormone Genes

“…observations]. These observations, along with the in creased abundance of corticotrophs in one of these lines [ 1] and the reports of increased ACTH levels in GH-treated rats [2] and of direct effects of GH and insulin-like growth factor-1 (IG F-1) on the adrenal cortex [3,4], raised a possibility that ectopic ex pression of heterologous GH genes may lead to stimulation of adrenocortical activity. To examine this possibility, we have measured plasma corticosterone levels and adrenal corticoste rone content under basal conditions and after standardized stressful stimulus.…”

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

“…Using a line of mice expressing the mouse metallothionein-1 (m MT)/human growth hormone (hGH) transgene, we have shown that the failure of pregnancy is associated with, and Received: April 24, 1990 Accepted after revision: September 17, 1990 most likely due to, the increased activity of the tuberoinfundibular dopaminergic system and the suppression of the postcoital rise in prolactin release [9]. Males from the same line are usually fertile but exhibit dramatic reductions in plasma prolactin levels [ 10] and in the number and secretory activity of lactotrophs [ 12], as well as significant increases in noradrenergic activity in the median emi nence [11], and in plasma LH levels [10,11], along with the appearance o f 'castration cells' in the adenohypophysis [12], From the nature of these abnormalities and from observa tions of relatively normal reproductive performance in mice ex pressing bovine or ovine GH genes [4; Yun, Wagner, Bartke and Naar, unpubl. observations], we suspected that the effects of m M T/hGH transgene expression are due largely, if not ex clusively, to the well-documented prolactin activity of hGH in rodents [13,14], In order to test this hypothesis, we have com pared various parameters of neuroendocrine function in mMT/ hGH transgenic mice and in mice expressing hGH variant…”