NEUROENDOCRINE AND REPRODUCTIVE CONSEQUENCES OF OVEREXPRESSION OF GROWTH-HORMONE IN TRANSGENIC MICE

Availability of recombinant growth hormone (GH) and development of lon g-acting formulations of this material will undoubtedly lead to widesp read use of GH in animal industry and in medicine. GH can act, directl y or indirectly, on multiple targets, but its influence on the reprodu ctive system and on the hormonal control of reproduction is poorly und erstood. Overexpression of GH genes in transgenic animals provides a u nique opportunity to study the effects of long-term GH excess. Transge nic mice overexpressing bovine, ovine, or rat GH (hormones with action s closely resembling, if not identical to, those of endogenous [mouse] GH), exhibit enhancement of growth, increased adult body size, and re duced life-span as well as a number of endocrine and reproductive abno rmalities. Ectopic overexpression of bovine GH (bGH) driven by metallo thionein or phosphoenolpyruvate carboxykinase promoters is associated with altered activity of hypothalamic neurons which produce somatostat in, loss of adenohypophyseal GH releasing hormone (GHRH) receptors, an d suppression of endogenous (mouse) GH release. Elevation of plasma le vels of GH (primarily bGH) and insulin-like growth factor (IGF-I) in t hese transgenic mice leads to increases in the number of hepatic GH an d prolactin (PRL) receptors, in the serum levels of GH-binding protein (GHBP), in the percent of GHBP complexed with GH, and in the circulat ing insulin levels. In addition, plasma adrenocorticotropic hormone (A CTH) and corticosterone levels are elevated. Plasma levels of luteiniz ing hormone (LH), as well as its synthesis and release, are not consis tently affected, but follicle-stimulating hormone (FSH) levels are sup pressed, apparently due to pre- and post-translational effects. Pituit ary lactotrophs exhibit characteristics of chronic enhancement of secr etory activity, and plasma PRL levels are elevated. Prolactin response s to mating or to pharmacological blockade of dopamine synthesis are a bnormal. Reproductive life span and efficiency are reduced in both sex es, with the severity and frequency of reproductive deficits being rel ated to plasma bGH levels. Most transgenic females expressing high lev els of bGH are sterile due to luteal failure. Overexpression of human GH which, in the mouse, interacts with both GH and PRL receptors leads to additional endocrine and reproductive abnormalities including stim ulation of LH beta mRNA levels and LH secretion, loss of responsivenes s to testesterone feedback, overstimulation of mammary glands, enhance d mammary tumorigenesis, and hypertrophy of accessory reproductive gla nds in males. Results of these studies indicate that GH can exert a va riety of direct and indirect actions at the hypothalamic, pituitary, g onadal, and reproductive tract levels, and that the consequences of pr olonged exposure to supraphysiological levels of GH cannot always be p redicted from the known or the presumed physiological actions of this hormone.