Naomi E Rance
Associate Department Head, Pathology
Professor, BIO5 Institute
Professor, Cellular and Molecular Medicine
Professor, Evelyn F Mcknight Brain Institute
Professor, Neuroscience - GIDP
Professor, Physiological Sciences - GIDP
My overall research objective is to characterize and understand the events that occur in the human central nervous system in response to menopause. An equally important goal is to contribute to our understanding of the neuroendocrine mechanisms that regulate reproduction. Although complex, the neural basis of reproductive function is amenable to experimentation because of the known feedback circuits. Control mechanisms can be studied at many different levels, ranging from plasma hormone levels, to gene expression in subsets of hypothalamic neurons.Menopause provides a unique opportunity to correlate physiology and neuroanatomy in the human brain because ovarian and pituitary hormones change dramatically and consistently. In the last decade, our laboratory has made considerable progress in characterizing changes in neuronal morphology and neuropeptide gene expression in the hypothalamus of postmenopausal women. We have found a number of changes that correlate with the ovarian failure of menopause. Neurokinin B and substance P gene expression is markedly increased in the infundibular nucleus of postmenopausal women, along with hypertrophy of these neurons. In addition, the gene expression of a separate subpopulation of LHRH neurons is increased in the medial basal hypothalamus of postmenopausal women. In contrast, POMC gene expression in the infundibular nucleus is decreased.These observations have provided the direction of our studies using animal models. For example, the rat was used to test the hypothesis that increased neurokinin B gene expression in the hypothalamus of postmenopausal women is secondary to gonadal failure. These studies showed that that long-term gonadectomy results in increased numbers of arcuate (infundibular) neurons expressing NKB gene transcripts in both males and females. We have also found that long-term orchidectomy results in significant dendritic growth in neuroendocrine neurons in the arcuate nucleus of adult male rats. These data suggested that the withdrawal of gonadal steroids ultimately results in a substantial remodeling of hypothalamic neuronal circuits. We have hypothesized that the hypertrophied NKB neurons participate in the hypothalamic control of LH secretion. Our recent studies using both pharmacological and physiological methods provide strong support for this hypothesis.Because menopause affects a well-characterized system and has consistent and substantial changes in hormone levels, our research program has been able to correlate alterations in hormone secretion with structural and neurochemical changes in the human hypothalamus. Our ability to address basic biological questions in the human CNS is greatly enhanced by the use of animal models to test hypotheses arising from our observations of the human hypothalamus. Characterization of the hypothalamic changes accompanying menopause has the potential not only of shedding light on the regulation of gonadotropin secretion and hypothalamic aging in the human, but may also have practical implications for the health of postmenopausal women.