ESTROGEN UP REGULATES TYROSINE HYDROXYLASE GENE IN MONKEY BRAINSTEM

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We have previously shown that in intact cycling rhesus monkeys, the surge in preovulatory estrogen is followed within 30 h by massive releases of gonadotropin-releasing hormone (GnRH) from the hypothalamus and luteinizing hormone (LH) from the pituitary. Also, exogenous estrogen treatment in ovariectomized (OVX) monkeys induces a preovulatory-like LH surge that is accompanied by a dramatic increase in hypothalamic release of norepinephrine (NE). We hypothesize that preovulatory release of NE from brainstem neurons is initiated by a sustained secretion of ovarian estrogen. The increased NE, in turn, triggers the release of GnRH which stimulates the LH surge. To test this hypothesis, we quantitated mRNA levels of tyrosine hydroxylase (TH, the rate-limiting enzyme of NE synthesis) in the locus coeruleus (LC, a brainstem area where NE cell bodies are located) of 5 OVX monkeys treated with a level of estrogen that is known to induce a LH surge. These results were compared with OVX animals either without estrogen (n = 5) or with a low estrogen milieu (n = 5) that does not induce a LH surge. Quantification of TH mRNA was carried out by in situ hybridization in thin sections of the LC after paraformaldehyde fixation. A rhesus monkey-specific TH cDNA fragment was cloned for use as a probe. A 15-fold increase occurred in TH gene expression in the LC of OVX monkeys treated with the LH-inducing regimen of estrogen as compared to the two control groups. The results suggest that an increase in TH transcription and translation in the LC is an integral part of the preovulatory neuroendocrine events surrounding NE/GnRH/LH release. Experiments are in progress to examine the gene expression of neuropeptide Y (NPY) and NE transporter (NET) in these animals. Both NPY and NET are colocalized with NE cells in the LC and are known to influence the secretion of GnRH, either individually or in conjunction with NE. The findings of these studies will enhance the understanding of how and where estrogen acts in the brain to trigger ovulation in the primate.