Effects of transgenes for human and bovine growth hormones on age‐related changes in ovarian morphology in mice

The expression of human growth hormone (GH) in female transgenic mice (TM) is accompanied by sterility, whereas females expressing the bovine GH gene are fertile. A light and electron microscopic study was conducted to examine whether expression of these foreign GH genes in mice is associated with structural changes in the ovaries of young adult (3-month-old) or middle-aged (7-month-old) mice. One ovary was serially sectioned for light microscopy, and the contralateral ovary was used for electron microscopy. The numbers of preantral (PAF) and antral (AF) follicles, with and without signs of atresia, as well as the number of corpora lutea (CL), were determined. As expected, body weights of both young and middle-aged TM of either kind were significantly increased over those of their normal littermates. However, the ovarian weights of TM and control mice did not differ. In the 3-month-old TM, the ovaries were grossly normal at the light microscopic level. However, significantly more CL were counted in the ovaries of human GH-TM than in those of the other two groups. The percentage of PAF with signs of atresia was significantly reduced in ovaries of bovine GH-TM compared with the other groups, while the percentages of AF undergoing atresia were significantly different in all groups, with the highest values in normal animals, intermediate ones in human GH-TM, and the lowest in bovine GH-TM. In the ovaries of 7-month-old human GH-TM, conspicous clusters of large, foamy light cells were present in the cortex and the medulla. Ultrastructurall, these cells appeared as interstitial cells in various stages of degeneration, accumulating cholesterol crystal-like inclusions. Although degeneration of interstital cells was observed also in the other types of animals, it involved usually only single cells and no cytoplasmic crystal inclusions. Moreover, in the ovaries of 7-month-old human GH-TM the percentages of PAF were significantly reduced and the percentages of AF significantly increased compared with those in the two other groups, which did not differ from each other with respect to these parameters. No significant differences in the numbers of CL were found between the groups. Percentages of atretic PAF were significantly reduced in bovine GH-TM and comparable in the other two groups, while percentages of atretic AF were not different between normal and bovine GH-TM, but were significantly increased in human GH-TM. Our results support the idea that the ovary, although not enlarged in either type of TM, is affected by chronic exposure to heterologous GH. Bovine GH, which in the mouse exhibits isolated somatotrophic activity, reduced the morphological signs of atresia in TM. Human GH, which in the mouse has additional lactotrophic activity, caused complex, age-related changes, including acceleration of follicular development, increased atresia, and massive degeneration of interstitial cells. These results suggest that the expression of human GH transgene leads to accelerated aging of the mouse ovary and that this effect is likely due to the combination of somatotrophic and lactotrophic activities of human GH in this species.