Functional disorders in luteinizing hormone-releasing hormone and A1 noradrenergic neurons in androgen-sterilized rats

Abstract

A single injection of androgen to 5-day old female rats renders these animals permanently sterile as adults. Previous studies suggest that the principle neuroendocrine malfunction in these androgen-sterilized rats (ASR) resides within the noradrenergic system and norepinephrine (NE) plays an important role in triggering preovulatory LHRH/LH surges. Although synaptic connections between NE and LHRH neurons are established prior to or at birth, it remains to be resolved whether these synapses are functional in ASR. In initial studies, we observed that the pituitary glands of ASR are less responsive to pulse injections of LHRH than normal rats. As well, responsiveness of LHRH neurons to electrochemical stimulation (ECS), icv infusion of norepinephrine (NE) or combined ECS + icv NE also are markedly diminished in ASR. When combined preoptic and A1 stimulations were performed, marked amplification of LH release occurred in both controls and ASR although less LH was released in ASR. Thus, LHRH-NE synapses are functional in ASR but the NE signal spontaneously is not presented to LHRH neurons. Consequently, spontaneous LH surges do not occur in ASR. LHRH neuronal responsiveness to NMDA stimulation also was found to be reduced in ASR. NMDA increased LHRH mRNA levels in the OVLT and rostral preoptic area in controls but not in ASR. These data suggest that a deficiency exists in the mechanisms responsible for transcription of LHRH mRNA in ASR. Other studies provided evidence that changes in levels of tyrosine hydroxylase (TH) mRNA in catecholamine neurons could serve as an index of increased activity within these cells. In proestrous rats, significant increases in TH mRNA levels were observed in A1 neurons during the afternoon hours when increases in hypothalamic NE turnovers occur. None of these events occurred in ASR. In summary, when the undifferentiated NE-LHRH-pituitary axis is exposed to high levels of androgen during a critical period in development, damage occurs at all levels within this axis to such an extent that spontaneous LH surges are permanently abolished and these animals become permanently sterile as adults.