REDUCTION OF TYROSINE HYDROXYLASE MRNA EXPRESSION IN MENOPAUSAL MONKEYS

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The menopausal syndrome in women includes hot flashes, sleeplessness, depression and increased cardiovascular difficulties. Each of these conditions impacts quality of life, and one underlying cause may be a malfunctioning of the catecholaminergic neuronal system, i.e., dopamine (DA), norepinephrine (NE) and epinephrine (EPI). In middle-aged rats, central neural NE deficiency contributes to decreased reproductive performance, slowed learning ability and reduced wheel-running activity. In primates, little is known about the changes in brain chemicals during and after onset of menopause, which is characterized by a cessation of ovarian activity, including the production of ovarian estrogens (E) and progestins. We have previously shown that E replacement in adult ovariectomized monkeys up-regulates the expression of tyrosine hydroxylase (TH, the rate-limiting enzyme of NE synthesis) mRNA in the locus coeruleus (LC) of the brainstem a structure that contains both NE cell bodies and multiple types of neuropeptides. Thus, we hypothesize that a reduction of catecholaminergic activity, in association with reduced circulating levels of E, accompanies menopause in rhesus macaques. To test this hypothesis, we examined the expression of TH mRNA in three perimenopausal (21-25 years of age) and three younger (7-14 years of age) female monkeys after treatment with E. We reasoned that the demise of the catecholaminergic system in perimenopausal monkeys would alter the up-regulation of TH gene expression by E. A rhesus monkey-specific TH probe (176 bp) was generated, sequenced, labeled with S-35 and applied to 20 m thin sections of the hypothalamus and brainstem for in situ hybridization. Positive TH mRNA signals were digitized and compared between the E-treated old and young animals. Preliminary data suggest that in the brainstem, the NE cells in the nucleus of the solitary tract (A2), the lateral tegmentum of the medulla (A1) and the LC (A6 and A4) expressed less TH mRNA in the perimenopausal females than in the younger individuals. Furthermore, expression of TH mRNA in the perimenopausal monkeys was reduced in dopaminergic neurons in the substantia nigra and lateral tegmentum of the mesencephalon. In the hypothalamus, the stria terminalis and paraventricular nuclei contained less, whereas the suprachiasmatic nucleus contained more TH mRNA in the older monkeys. These preliminary observations support the concept of a disrupted balance between ovarian E and brain catecholaminergic neurons during perimenopausal changes. We plan to continue the study of these and other brains from similar aged monkeys and ultimately to develop a monkey model for characterization of ovarian and central neural deficits in women before and during onset of menopause.