INFERTILITY IN TRANSGENIC MICE OVEREXPRESSING THE BOVINE GROWTH-HORMONE GENE - DISRUPTION OF THE NEUROENDOCRINE CONTROL OF PROLACTIN SECRETION DURING PREGNANCY

Transgenic female mice overexpressing the bovine growth hormone (bGH) gene with the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhib it severe reproductive deficits. Although these animals ovulate and co nceive normally, pregnancy is arrested due to luteal failure, leading to the loss of embryos during early gestation. The results of replacem ent therapy suggested that luteal failure was secondary to prolactin ( PRL) deficiency. The objective of this study was to examine the neuroe ndocrine control of PRC secretion during early pregnancy in PEPCK.bGH- 1 transgenic mice. Normal and transgenic littermates were killed by de capitation on Day 7 postcoitum (p.c.) at 1500, 1800, or 2100 h, i.e., the period including the expected diurnal PRL surge in pregnant mice. In normal females, plasma PRL levels were significantly elevated at 18 00 h when compared to the levels measured at 1500 or 2100 h, but no te mporal variation in PRL levels was found in transgenic mice. In normal females, the content of dopamine in the median eminence was reduced a t 1800 h, i.e., at the time of the PRL surge. In contrast, no temporal changes were detected in the median eminence dopamine content in tran sgenic mice. Twice-daily injections of domperidone, a dopamine recepto r blocker, increased the incidence of pregnancy in transgenic females. After treatment with aromatic amino acid decarboxylase inhibitor NSD- 1015 on Day 7 p.c., plasma levels of PRL were similarly elevated in tr ansgenic and normal females. However, the accumulation of 5-hydroxytry ptophan (5-HTP) in the medial basal hypothalamus after this treatment was significantly smaller in transgenic than in normal females. We con clude that luteal failure in PEPCK.bGH transgenic mice is secondary to the absence of an optimal pattern of PRL secretion during pregnancy, even though the pituitary produces adequate quantities of PRL. The app arent suppression of PRL surges in transgenic females appears to be du e to persistence of the tonic dopaminergic inhibitory tone at the time when the PRL surge would normally occur. The failure of dopaminergic activity to decline at the time of the PRL surge in transgenic females may be related to reduced serotonergic input to the hypothalamus.