Fertility of female transgenic mice expressing the bovine growth hormone gene

Female mice overexpressing the phosphoenolpyruvate carboxykinase/bovine growth hormone (PEPCK.bGH) gene have severe deficits in reproductive function. These animals have slightly prolonged but regular estrous cycles and ovulate increased numbers of ova. However, approximately 85% of transgenic females that have mated fail to maintain pregnancy beyond day 7. Progesterone levels are reduced on days 2 and 7 post coitum in transgenic females as compared to their normal littermates. However, there were no differences in plasma progesterone at either day in transgenic females that were found to be pregnant at day 7 when compared to the ones that were not. Progesterone injections (1 mg/day) maintain pregnancy in virtually all animals. Twice daily PRL injections in a schedule designed to mimic the prolactin surges of pregnancy increased pregnancy rate in transgenic females to the level comparable to that seen in normal animals. To test the possibility that transgenic females are infertile due to the absence of the mating-induced PRL surges, transgenic and normal females were killed at 15:00, 18:00 and 21:00 h on day 7 post coitum. Normal females had sharply increased PRL levels at 18:00 h while in transgenic females there was no evidence of a PRL surge at this time. However, pituitary PRL content did not differ between normal and transgenic females at any of the times examined. Dopamine content in the median eminences of normal females was reduced at 18:00 as compared to 15:00 and 21:00 h. No time-related changes were found in dopamine levels in median eminences of transgenic mice. Blockade of dopamine receptors in PEPCK.bGH females by domperidone injected in the same schedule as PRL also produced pregnancy rate similar to that found in normal females. Accumulation of the serotonin precursor 5-HTP in the medial basal hypothalamus after dopa decarboxylase inhibition on day 7 post coitum was higher in normal than in transgenic females. We conclude that infertility of female transgenic mice overexpressing bGH is due to luteal failure secondary to the absence of the mating-induced PRL surges. Inhibition of prolactin release is not at the pituitary level, as was previously demonstrated in mice transgenic for hGH, since in animals expressing bGH, PRL content is not altered and blockage of dopamine receptors produces normal pregnancy rates. The results also suggest that the failure of median eminence dopamine stores to be depleted at 18:00 h may be due to alterations in hypothalamic serotonergic transmission.